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Basal ganglia and autism - a translational perspective: Basal ganglia and autism

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Lay summary: Habit learning, action selection and performance are modulated by the basal ganglia, a collection of groups of neurons located below the cerebral cortex in the brain. In autism, there is emerging evidence that parts of the basal ganglia are structurally and functionally altered disrupting normal information flow. The basal ganglia through its interconnected circuits with the cerebral cortex and the cerebellum can potentially impact various motor and cognitive functions in the autism brain.
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REVIEW ARTICLE
Basal Ganglia and Autism – A Translational Perspective
Krishna Subramanian , Cheryl Brandenburg, Fernanda Orsati, Jean-Jacques Soghomonian ,
John P. Hussman, and Gene J. Blatt
The basal ganglia are a collection of nuclei below the cortical surface that are involved in both motor and non-motor
functions, including higher order cognition, social interactions, speech, and repetitive behaviors. Motor development
milestones that are delayed in autism such as gross motor, fine motor and walking can aid in early diagnosis of
autism. Neuropathology and neuroimaging findings in autism cases revealed volumetric changes and altered cell den-
sity in select basal ganglia nuclei. Interestingly, in autism, both the basal ganglia and the cerebellum are impacted
both in their motor and non-motor domains and recently, found to be connected via the pons through a short disy-
naptic pathway. In typically developing individuals, the basal ganglia plays an important role in: eye movement,
movement coordination, sensory modulation and processing, eye-hand coordination, action chaining, and inhibition
control. Genetic models have proved to be useful toward understanding cellular and molecular changes at the synap-
tic level in the basal ganglia that may in part contribute to these autism-related behaviors. In autism, basal ganglia
functions in motor skill acquisition and development are altered, thus disrupting the normal flow of feedback to the
cortex. Taken together, there is an abundance of emerging evidence that the basal ganglia likely plays critical roles in
maintaining an inhibitory balance between cortical and subcortical structures, critical for normal motor actions and
cognitive functions. In autism, this inhibitory balance is disturbed thus impacting key pathways that affect normal
cortical network activity. Autism Res 2017, 0: 000–000.V
C2017 International Society for Autism Research, Wiley
Periodicals, Inc.
Lay Summary: Habit learning, action selection and performance are modulated by the basal ganglia, a collection of
groups of neurons located below the cerebral cortex in the brain. In autism, there is emerging evidence that parts of
the basal ganglia are structurally and functionally altered disrupting normal information flow. The basal ganglia
through its interconnected circuits with the cerebral cortex and the cerebellum can potentially impact various motor
and cognitive functions in the autism brain.
Keywords: basal ganglia; animal models; motor, autism; neuroanatomy; neuroimaging; neuropathology
Introduction
The basal ganglia (BG), a collection of subcortical nuclei
including the caudate, putamen, nucleus accumbens,
globus pallidus (GP), and subthalamic nucleus (See Box
1), are involved in the acquisition, selection, and per-
formance of learned habits, actions and action sequen-
ces [Graybiel, 2008; Graybiel & Grafton, 2015; Jin &
Costa, 2015; Jin, Tecuapetla, & Costa, 2014; Yin &
Knowlton, 2006]. The BG participates in a vast array of
sensorimotor and cognitive functions, some of which
are altered in many clinical conditions. For example,
striatal toes, a spontaneous upward movement of big
toes commonly seen in patients with Parkinson’s dis-
ease, is also seen in autism [Damasio & Maurer, 1978].
Some symptoms observed after BG or thalamic lesions
ABBREVIATIONS: 5-HT, 5-Hydroxytryptamine; AcH, AcetylCholine; AMPA - a, amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor;
BDNF, Brain Derived Neurotrophic Factor; C/CAU, Caudate nucleus; CNTNAP, Contactin-Associated Protein-Like (CNTNAP); CT Neurons, Cortico-
Thalamic Tract Neurons; D1R, Dopamine receptor type 1; D2R, Dopamine receptor type 2; DN, Dentate Nucleus; FEF, Frontal Eye Fields (FEF);
GABA-A Ç, Aminobutyric Acid receptor type A; GABA-B Ç, Aminobutyric Acid receptor type B; GPe, Globus Pallidus externa; GPi, Globus Pallidus
interna; IT-CC Neurons, Intratelencephalic Cortico-cortical Neurons; IT-CStr Neurons, Intratelencephalic Cortico-striatal Neurons; LIP, Lateral Intra-
Parietal area; mGluR, metabotropic glutamate receptors; MSN, Medium Spiny Neurons; NAc, Nucleus Accumbens; NMDA, N-methyl-D-aspartate
receptor; PN, Pontine Nucleus; PNS, Peripheral Nervous System; PPN, Pedunculo Pontine Nucleus; PT Neurons, Pyramidal Tract Neurons; Pu/PUT,
Putamen; SC, Superior Colliculus; SEF, Supplementary Eye Field; SHANK, SH3 and multiple ankyrin repeat domains 3 (Shank3), also known as
proline-rich synapse-associated protein 2 (ProSAP2); SNpc, Substantia Nigra pars compacta; SNpr, Substantia Nigra pars reticulata; STN, Subthalamic
Nucleus; Trk B, Tyrosine kinase receptor type B; VTA, Ventral Tegmental Area
From the Program on Neuroscience, Hussman Institute for Autism, Baltimore, MD 21201 (K.S., C.B., J.P.H., G.J.B.); Program on Supports, Hussman
Institute for Autism, Catonsville, MD 21228 (F.O., J.P.H.); Department of Anatomy & Neurobiology, Boston University School of Medicine, Boston,
MA 02118 (J.-J. S.)
Received May 30, 2017; accepted for publication June 23, 2017
Address for correspondence and reprints: Krishna Subramanian, Ph.D., Program on Neuroscience, Hussman Institute for Autism, 801 W. Baltimore
Street, Suite 301, Baltimore, MD 21201. E-mail: myemailiskrishna@gmail.com
Published online 00 Month 2017 in Wiley Online Library (wileyonlinelibrary.com)
DOI: 10.1002/aur.1837
V
C2017 International Society for Autism Research, Wiley Periodicals, Inc.
INSAR Autism Research 00: 00–00, 2017 1
resemble behaviors in autism such as akinesia of the
face, emotional facial asymmetry prominently present
during spontaneous smile and speech, agonist-
antagonist imbalance in muscle tone, dystonia of the
extremities, movement difficulties (bradykinesia and
hyperkinesia, slow and fast movements), rhythmic flap-
ping, chorea, atheosis, or both (chorea-atheosis) with
some repeated stereotypical complex hand movements,
and gait alterations comparable to those seen in parkin-
sonian patients [Damasio & Maurer, 1978; Vilensky,
Damasio, & Maurer, 1981]. More recently, an increased
risk for Parkinsonism (20–27%) was observed in individ-
uals with autism compared to the general population
(0.1–0.9%) [Starkstein, Gellar, Parlier, Payne, & Piven,
2015]. Development of social isolation, altered encod-
ing of social rewards, apathy, reduced spontaneity,
aboulia, lack of expressive emotional affect, obsessive-
compulsive behaviors, or in some situations akinetic
mutism in typically developing individuals can follow
immediately after lesions of the BG and all may in part
resemble the social and communication alterations
seen in some individuals with autism [Bhatia & Mars-
den, 1994; Damasio, Damasio, Rizzo, Varney, & Gersch,
1982; Miller et al., 2006; Ramirez-Zamora, Ramani, &
Pastena, 2015]. Thus, the motor, social and communi-
cation challenges seen following BG lesions parallel the
criteria that define autism. Due to these reasons the
neuropathological, clinical, physiological, and neuro-
chemical changes within the autism BG could be criti-
cal substrates to comprehensively contribute to the
understanding of phenotypic profiles.
Unlike the cerebral cortex, the vast majority of neu-
rons in the BG is inhibitory and use GABA as their pri-
mary neurotransmitter. These neurons participate in
major multi-synaptic inhibitory and excitatory feedback
pathways to the cortex. However, alterations in the BG
and their potential contribution to various motor, asso-
ciative and cognitive behaviors observed in autism have
not been clearly elucidated. Here, we review the neuro-
pathological basis of BG alterations in the autism brain
(Section A) followed by clinical aspects of autism-
associated behaviors and their relationship to the BG
(Section B). Next, we examine proposed animal models
of autism and their relationship to BG (Section C).
Finally, a proposed model of the overall sub-cortical
inhibitory circuit changes (Section D) are presented
BOX 1: Basal Ganglia – A Primer
The basal ganglia (BG) are a collection of sub-cortical structures that form a highly interconnected network of several nuclei in
the forebrain, midbrain and thalamus (Fig. 1a). The BG were originally thought to be involved in motor control and execution
[Alexander & Crutcher, 1990]. However, with advances in neuroanatomical tracing and our renewed appreciation for the roles of
the different regions based on their connectivity and functions, a number of non-motor behaviors (i.e., habits, emotions, moti-
vation, sleep, and cognitive function) are also attributed to the BG [Graybiel, 2008; Haber & Knutson, 2010; McDowell & Chesse-
let, 2012; Yin & Knowlton, 2006].
The following are the components of the basal ganglia. The names of these nuclei have been used throughout this review.
The striatum is comprised of the dorsal and ventral striatum and is the major region of recipient inputs to the BG. The nuclei
within the striatum are: the caudate, putamen (C/Pu) and the nucleus accumbens, which is comprised of core and shell territo-
ries (NAc core/shell). The GP consists of the external segment (GPe) and the internal segment (GPi). The output of the BG is
from the GPi to the thalamus with the exception that output from eye movement circuits in the BG project from the substantia
nigra pars reticulata (SNpr).
The substantia nigra pars compacta (SNpc) and ventral tegmental area (VTA) are the two main dopaminergic midbrain projec-
tions. The C/Pu, NAc core/shell, GPe, and GPi/SNpr are primarily comprised of GABAergic nuclei with GABAergic projection neu-
rons. The sub-thalamic nucleus (STN) is the only glutamatergic nucleus in the BG with glutamatergic projection neurons.
Neuroanatomical tracing studies have shown parallel motor and non-motor anatomical and functional networks from the cortex
to the BG as well as connections from the BG to the cerebellum. The projections to the BG from the motor cortex, pre-motor cor-
tex, dorsolateral prefrontal cortex (dlPFC), dorsal anterior cingulate cortex (dACC), orbitofrontal cortex (OFC) and ventromedial
prefrontal cortex (vmPFC) are organized topographically from the dorsal to the ventral BG regions, respectively (Fig. 1b). These
projections can also be grouped into the functional territories of motor, associative/sensorimotor and cognitive areas in the BG
(Fig. 1c).
The canonical direct, indirect and hyper-direct pathways from the cortex to the BG are described, along with the recently dis-
covered disynaptic projection to the cerebellar cortex from the STN in Figure 1d [Bostan et al., 2010; Bostan, Dum, & Strick,
2013]. One functional circuit is taken as an example for representative purposes namely Area 46, which is involved in cognition
and connects with both the BG and cerebellum (Fig. 1d). The same area in the cerebellar cortex, Crus II, receives projections
from the STN [Bostan et al., 2010] and receives and sends projections to cortical Area 46 (Fig. 1d) [Kelly & Strick, 2003]. There
are similar functional circuits that are proposed to exist in parallel (Fig. 1c), which are also interconnected with each other (Fig.
1b) and the cerebellum (Fig. 1d).
2 Subramanian et al./Basal ganglia and autism INSAR
that would impact cortical functions and provide leads
to new interventions that could benefit individuals
with autism and their families.
A. Basal Ganglia in Autism: Neuropathological Studies
Neuropathological studies of the dorsal and ventral stri-
atum in individuals with autism are extremely sparse.
The most comprehensive analysis of a Nissl stained
postmortem tissue study was conducted by Wegiel and
colleagues in 14 brains from individuals with autism
compared to 14 age-matched controls [Wegiel et al.,
2014]. In individuals aged from 9 years to 60 years,
these authors found, in the autism group, a 22%
increase in the volume of the caudate nucleus and a
34% increase in the volume of the nucleus accumbens
(NAc). In contrast, these same structures from young
individuals with autism aged 4–8 years did not exhibit
any differences in volume suggesting that the changes
in volumes may be occurring from adolescence into
adulthood [Wegiel et al., 2014]. The putamen and GP
(external and internal segments) in these same individ-
uals did not show any difference in volume in the
autism group at any age. Stereological analysis of these
dorsal and ventral striatal structures revealed significant
decreases in neuronal density in the NAc and the puta-
men but normal neuronal density in the caudate
nucleus and both segments of the GP [Wegiel et al.,
2014].
In parallel to the neuropathological study by Wegiel
and colleagues, Sato et al. [2014] conducted an MRI
study measuring the volume of the component parts of
the BG in 29 adults with autism (Asperger’s and PDD-
NOS) without intellectual disabilities compared to 29
age- and gender-matched control individuals. From T-1
weighted anatomical images, these authors reported a
significant increase in putamen volume but normal vol-
umes in the caudate nucleus, NAc and GP. Further, the
increases in putamen volumes were significant in both
the left and right hemispheres [Sato et al., 2014].
The disparate findings in the above two studies is
reflective of one of the major problems scientists face
when comparing neuroanatomical findings to reports
from imaging studies. On one hand, the postmortem
cohorts usually derive from individuals with more com-
plex and challenging autism conditions, whereas imag-
ing studies include mainly individuals that are verbal
and deemed “high functioning,” who experience less
severe symptoms but may have social difficulties. The
underlying question that remains unanswered is how
much overlap there is with regard to changes in brain
structures amongst the two groups, considering that
many individuals in the “autism” group may also be
very competent in intellectual abilities, but have diffi-
culty communicating their thoughts and regulating
behavior and social interaction. If the two studies
described are any indication, it suggests that there are
indeed differences in the development of striatal cir-
cuitry. With the complexities of BG structures and
accompanying connectivity with prefrontal, cingulate,
pre-motor, and motor cortices, such differences in the
autism cohorts may have significant and striking differ-
ences that affect a wide variety of behaviors ranging from
repetitive/stereotyped movements, social-emotional
behavior, self-reward, and/or non-motor functions. In
addition, limbic areas including the anterior cingulate
cortex that sends projections to the striatum has been
shown in individuals with autism to have a marked
reduction in the number of GABA-A receptors [Oblak,
Gibbs, & Blatt, 2009] as well as decreased density of
GABA-B receptors [Oblak, Gibbs, & Blatt, 2010] and select
serotoninergic receptor subtypes [Oblak, Gibbs, & Blatt,
2013]. This imbalance of neurochemical circuitry within
the anterior cingulate may contribute to altered excit-
atory input to striatal areas thus influencing its normal
function(s). Nevertheless, a review of key imaging studies
of the BG is very informative, especially in the higher
performance autism group.
An interesting correlation of structural connectivity
via diffusion tensor imaging (DTI) of fronto-striatal cir-
cuitry and inhibitory control was conducted by Langen
et al. [2012]. These authors found that adults with
autism had reduced total brain white matter volume
and decreased functional anisotropy of white matter
tracts connecting the putamen with frontal cortical
regions, and higher mean diffusivity of white matter
tracts connecting NAc to frontal cortex [Langen et al.,
2012]. The latter also had worse performance on a go/
no go task suggesting that autism may be associated
with differences in the anatomy of fronto-striatal white
matter tracts. Previously, Di Martino et al. [2011] found
hyperconnectivity between the striatum and the pons
as well as increased functional connectivity between
striatal areas and associative and limbic cortices.
A study of BG morphology and repetitive behavior in
children aged 3–4 years with autism compared to a
cohort with developmental delay (DD) and with
another group of typically developing children (TD)
was performed by Estes, Shaw, and Sparks [2011]. In
that study, enlargement of striatal structures including
left and right putamen and left caudate nucleus was
found in the autism group when compared to the other
two groups. However, higher levels of repetitive/stereo-
typed behavior were correlated with decreased volume
in specific BG structures in the autism cohort including
the right and left putamen, right GP, and right striatum
when not adjusted for total cerebral volume. Decreased
volume of the GP was also demonstrated in a large
structural MRI study of individuals with autism com-
pared to controls [Sussman et al., 2015]. In a previously
INSAR Subramanian et al./Basal ganglia and autism 3
reported study, increased caudate nucleus volume was
positively correlated with repetitive/stereotyped behav-
iors [Hollander et al., 2005].
The relationship between the basal ganglia and
the cerebellum, two areas impacted in autism.
The BG and the cerebellum have long been thought to
take part in separate neural networks. However, each
network participates in goal-directed movements and,
more recently, overwhelming evidence has emerged for
a role in high-order cognitive functions [reviewed in:
Hampson & Blatt, 2015]. When activation patterns are
considered from imaging studies or early gene expres-
sion studies, there is recent evidence that these two
major brain networks may interact closely to regulate
high-order motor and non-motor functions.
Herrera-Meza et al. [2014] tested in rats the hypothe-
sis as to whether there are alterations in cerebellar acti-
vation patterns using cFOS expression when
stimulating or suppressing dopaminergic activity in the
substantia nigra pars compacta (SNpc). Briefly, acute
stimulation of SNpc by picrotoxin produced increased
cFOS expression in the vermis and cerebellar hemi-
spheres, but suppression by lidocaine had no effect.
Drug treatment by haloperidol for 2 weeks, or chronic
dopamine antagonism resulted in differential effects in
the vermis and cerebellar hemispheres suggesting that
with respect to dopamine alterations in the SNpc, there
are functional relationships between the BG and cere-
bellum [Herrera-Meza et al., 2014].
Dopaminergic input to the cerebellum was described
by Panagopoulos, Matsokis, and Valcana [1988] and, in
a later study, by the same group of investigators in the
reeler and weaver cerebellar mutant mice. These investi-
gators identified D1 receptors on granule cells and D2
receptors postsynaptically on granule cells and presyn-
aptically on dopaminergic fibers [Panagopoulos, Matso-
kis, & Valcana, 1993]. The authors speculated that the
extensive alterations in the dopaminergic systems in
both the cerebellum and striatum in the two homozy-
gous mutants may both contribute to the functional
control of movement underlying the observed
dyskinesias.
Recently, our understanding of the physiological rela-
tionship between the cerebellum and striatum has sig-
nificantly improved. Once thought to only
communicate with each other via a slow multi-synaptic
cortical loop, Chen, Fremont, and Arteaga-Bracho
[2014] revealed a short latency di-synaptic pathway in
mice whereby the cerebellum can rapidly modulate the
activity of the BG. This allows the BG to incorporate
the time-sensitive cerebellar signals into its output flow
to the cerebral cortex and acts to optimize motor con-
trol. The BG-CB relationship in motor control implies
that although each has distinctive roles in motor
behavior, their complementary functions and
interactions create a well-coordinated innervation to
motor cortical areas [Chen et al., 2014]. Another report
by Bare
s et al. [2015] in the rat, describes a powerful
short latency circuit connecting the cerebellar dentate
nucleus with the dorsolateral striatum, an area of the
BG thought to be involved with habit formation [Bare
s
et al., 2015; Yin & Knowlton, 2006; Yin, Knowlton, &
Balleine, 2004] suggesting that the cerebellar output
may be modulating such activity. It is still not clear,
however, how disrupting cerebellar development influ-
ences physiological activity within key circuitries such
as the striato-cortical pathways.
In autism, where there are many reports of reduced
numbers of Purkinje cells [Bailey et al., 1998; Bauman
& Kemper, 1985; Kemper & Bauman, 1998; Ritvo et al.,
1986; Whitney, Kemper, Bauman, Rosene, & Blatt,
2008; Williams, Hauser, Purpura, DeLong, & Swisher,
1980] especially those in the lateral hemisphere [Bau-
man & Kemper, 1985; Blatt & Fatemi, 2011; Skefos
et al., 2014; Whitney et al., 2008] that normally project
to the dentate nucleus, altered dentate output to the
BG and thalamus may be disrupting modulation of
striatal signals. This is especially noteworthy since the
remaining Purkinje cells in the cerebellum of individu-
als with autism contain reduced levels of GAD67 mRNA
[Yip, Soghomonian, & Blatt, 2007], and a subpopula-
tion of inhibitory dentate neurons have decreased
GAD65 mRNA [Yip, Soghomonian, & Blatt, 2009] con-
tributing to an alteration in excitatory: inhibitory (E:I)
balance in the autism brain [Blatt et al., 2001; Huss-
man, 2001]. Since the striatum and the subthalamic
nuclei directly connect with the deep cerebellar nuclei
[Bostan, Dum, & Strick, 2010] as well as many cortical
structures affected in autism, it is likely that the E:I bal-
ance in the BG is also altered.
In another study, Murphy et al. [2014] devised an
fMRI sustained attention task in which 46 typically
developing participants were compared to 44 individu-
als with autism. Each participant underwent 12 min of
a continuous attention task, with various built in
delays, to a visual stimulus (button press within 1 sec of
the appearance of the stimulus). Event acquisition data
revealed a significant delay in reaction time by the
autism group and greater inter-participant variability,
but no significant grouping-by delay effect was
observed. In the autism group, there was decreased acti-
vation of the left and right caudate/putamen, vermis
and cerebellar hemispheres, as well as various temporal
and frontal lobe areas. From the age of participants
tested, these authors concluded that individuals with
autism have sustained attention challenges associated
with and underlying altered functional brain matura-
tion between late childhood and adulthood [Murphy
et al., 2014] affecting both the BG and cerebellum.
4 Subramanian et al./Basal ganglia and autism INSAR
Recently, Dasgupta, W
org
otter, and Manoonpong
[2014] reported from the animal model literature that
the BG and cerebellum have complementary roles in
goal directed behavior, working in parallel but also
interacting with each other, guided by the thalamus. In
a computational model, these authors suggest that the
reward modulated heterosynaptic plasticity in the thal-
amus effectively balances the outcomes of the feed-
forward correlation based learning from the cerebellum
with the recurrent neural network model of the BG
[Dasgupta et al., 2014]. Hence, the artificial model of
combined learning by the two systems results in more
efficient goal-directed behaviors, and imbalances
between the two systems could contribute to alterations
in motor and non-motor functions.
B. Basal Ganglia in Autism – A Clinical Perspective on
Autism Behaviors
Based on evidence from neuropathological and neuro-
imaging studies (Section A) as well as from animal mod-
els (see Section C), the BG is emerging as a contributor
to autism condition. Since BG interactions with cortical
and subcortical regions are widespread, it is poised to
influence a wide range of motor and cognitive func-
tions [For review see: Leisman, Braun-Benjamin, &
Melillo, 2014]. This section outlines the potential influ-
ence of BG circuitry on core autism characteristics.
Although emphasis is placed on BG circuitry in specific
motor and cognitive functions, it does not exclude con-
tributions from other brain areas that participate in the
same functions. In an effort to disentangle the compli-
cated web of behaviors that lead to a diagnosis of
autism, this section begins with a discussion of motor
function challenges, followed by associative/sensorimo-
tor characteristics and, finally, inhibitory control. Most
of the clinical studies described in this section discuss
the performance of individuals with autism whose cog-
nitive skills can be assessed by traditional intellectual
quotient measures. However, our discussions extend to
the entire autism spectrum. Each of the core character-
istics outlined below and in Table 1 are major findings
that correlate with clinical observations in autism.
These characteristic behaviors are either modulated by
or are well-described components of BG function.
Clinical research studies demonstrate that people
with autism display a broad range of behaviors that are
closely influenced by their individual patterns of move-
ment and actions. Due to motor disturbances during
development, individuals with autism could respond
differently to stimuli in the environment based on their
individual compensatory motor mechanisms [Torres,
Yanovich, & Metaxas, 2013]. Traditional diagnosis and
clinical research classifies autism based on communica-
tion and social interaction challenges as well as
repetitive/stereotypic behaviors [Fung & Hardan, 2014].
Analyzing these large categories such as social skills, as
well as cognitive, behavioral, and emotional differences
has led to advances in diagnosis, description, treatment,
and supports for individuals with autism. However,
clinical observations within these categories are too
broad and do not provide specific or useful descriptions
for the previously noted heterogeneous characteristics
and performances in autism [Brincker & Torres, 2013].
Therefore, judging performance solely on clinical obser-
vations might not account for more specific compensa-
tory mechanisms developed by individuals to cope and
adapt to their external environment [Torres et al.,
2013]. There could be common underlying elementary
causes for the multitude of behaviors observed, such as
motor changes stemming from eye tracking and disrup-
tion in the coordination of movements that are the
building blocks of complex behaviors [Brenner, Turner,
&M
uller, 2007]. Shifting the focus from observing
more complex behaviors to more elemental subtle dif-
ferences that are common across individuals with
autism may help identify the underlying basis for core
characteristics of social and communication challenges
[Torres et al., 2013]. In addition, this closer look could
guide support strategies for autism that are based on
underlying neurobiological differences.
Goal-directed movements to environmentally salient
cues, especially voluntary movements by infants, are
the first medium of communication with care-givers,
which lead to harmonious motor development through
anticipation, coordination and adaptation as they
develop [Schmitz, Martineau, Barth
el
emy, & Assaiante,
2003]. Consequently, language and communication dif-
ferences in autism can be better understood when all of
the ingredients for language acquisition are considered,
such as eye movements and their coordination for
visual perceptual processing [Brenner et al., 2007].
Developmentally, these first basic functions are of para-
mount importance to learn more complex skills that
will aid in interaction with the external world [Iverson,
2010; Iverson & Fagan, 2013; LeBarton & Iverson,
2016].
Eye movement.Eye movement is a fundamental
building block of human development, with saccade
(sometimes referred to as gaze) being one of the most
well studied of these. A saccade is a rapid movement of
the eye that purposefully brings images to the center of
the eye (fovea) where they can be processed with higher
acuity. Nuclei of the BG shown to be involved with sac-
cade activity include the substantia nigra pars reticulata
(SNpr), [Basso & Liu, 2007; Handel & Glimcher, 1999;
Hikosaka & Wurtz, 1983; Joseph & Boussaoud, 1985],
caudate nucleus [Hikosaka & Sakamoto, 1989] and sub-
thalamic nucleus (STN) [Matsumura, Kojima, Gardiner,
& Hikosaka, 1992]. However, more recent evidence
INSAR Subramanian et al./Basal ganglia and autism 5
Table 1. Core Characteristics, Their Descriptions, Relevant Primary and Secondary Clinically Observed Behaviors and Their Selected Relevant References in Autism as
Well as References Implicating Basal Ganglia Involvement with These Characteristics
Core characteristics in autism
Primary behaviors observed and/
or its impact in autism
Secondary and downstream
changes
Selected References for Autism
Characteristics
Selected References for Basal
Ganglia Involvement:
Eye Movements
Oculomotor control with
purposeful movement and
its coordination for visual
processing
Visual search and visual
attention
Gaze movement toward people
and objects
Imitation
Joint attention
Social Interactions
Brenner et al. [2007] Basso and Liu [2007], Hikosaka
[2007], Watanabe and Munoz
[2011]
Eye-hand coordination
Coordination of visual gaze
in combination with pur-
poseful coordinated move-
ment of hands
Goal-directed behaviors
(reaching, opening, feeding,
pointing, handwriting, walk-
ing, etc.)
Different social activities
(games, playing ball, etc.)
Academic skills (writing, read-
ing pointing to right answer,
etc.)
Using alternative means to
communicate that require
pointing
Crippa et al. [2013], Iverson
[2010], Glazebrook et al.
[2009], Yu and Smith [2013]
Sailer et al. [2000]; van Donke-
laar and Staub [2000]
Movement coordination
Movement performance
alterations
Movement preparation
Upper extremity motor func-
tion (speed and latency)
Gait and balance
Postural control and mobility
Hypotonia
Apraxia
Body schema
Shared Engagement
Initiating a response
Fournier, et al., 2010; Ming
et al., 2014; Torres et al.,
2013
Barter et al. [2014], Seidler
et al. [2004]
Action chaining
Anticipate perceptual rep-
resentations and integrate
motor planning with motor
control of action
sequences
Goal directed behaviors
Need for constant prompts to
multiple step activity
Getting lost in the middle of an
activity
Following and engaging in
social interactions (play, con-
versations, games, etc.),
Language and communication
Haswell et al. [2009], Schmitz
et al. [2003], Stoit et al.
[2013], Forti et al. [2011]
Balleine et al. [2015], Frank
et al. [2009], Friend and Kra-
vitz [2014], Nagano-Saito
et al. [2014], Tanaka et al.
[2004], Wymbs et al. [2012],
Jin at al. [2014]
Sensory modulation and
processing
Reaction to multiple or
overwhelming sensory
stimulation from the
environment
Avoidance of environments or
activities that involve sound/
noise, different textures, light,
visual stimuli, food avoidance
Sensory seeking activities
(flapping, jumping, etc.)
Restrictive and unusual
interests
Reliance on the same routine
Social isolation and
withdrawal
Escape of environments
Self-stimulatory behaviors
Klintwall et al. [2011], Tavassoli
et al. [2014], Wiggins et al.
[2009]
Haber [2003], Nagy at al.
[2006], Reig and Silberberg
[2014], Yin [2010]
Inhibition control
Ability to inhibit a
response to other extrane-
ous incoming stimuli while
performing a goal
Impulsiveness
Suppressing unwanted stimuli
Inhibiting responses
Task switching
Repetitive behaviors and
routines
Inaccuracy (errors) in
performance
Christ et al. [2007], Geurts
et al. [2009], Mostert-
Kerckhoffs et al. [2015]
Jahanshahi et al. [2015],
Schmidt et al. [2013], Van
Schouwenburg et al. [2015]
The Observed Primary and Secondary Behaviors Are Separated into Different Categories for Illustrative Purposes While, in Reality, They Are Interconnected and Could Belong to Different Facets of
a Single Complex Behavior Cutting across Functional Categories.
6 Subramanian et al./Basal ganglia and autism INSAR
extends saccade control to include the putamen, GP
interna (GPi), pedunclopontine nucleus, and thalamus
[Watanabe & Munoz, 2011]. Neurons in the superior
colliculus (SC) receive inputs from multiple cortical
areas involved in eye movements including the frontal
eye fields, supplementary eye fields, and lateral intra-
parietal area [Watanabe & Munoz, 2011]. All of the cor-
tical excitatory inputs combined with the BG inhibitory
output from SNpr lead to burst firing of SC neurons
that signal downstream brainstem saccade generators
[Hikosaka, 2007]. Hikosaka [2007] further argues that
saccadic eye movements are likely modified by the BG
in the presence or absence of reward-related informa-
tion and suggests an involvement of dopamine in
reward modulation of saccadic eye movements by
encoding reward prediction error.
The integrity of basic oculomotor functions are com-
promised in autism and manifest as differences in sac-
cade latency, accuracy, inhibition, and disinhibition of
purposive saccadic generation, as well as smooth pur-
suit of a target [Brenner et al., 2007]. This delay in
motor behaviors during development in autism extends
into cognitive domains, such as initiated joint attention
(IJA). Furthermore, dopaminergic gene variants have
been suggested to affect IJA in siblings at high risk for
autism [Gangi, Messinger, Martin, & Cuccaro, 2016].
The ability to shift gaze toward other people, objects, or
changes in the surrounding environment as well as the
ability to follow another child’s attention or to follow
letters that form a word, are essential first steps to
higher order processes such as joint attention, shared
engagement, memory, reading, language development,
and communication [Mosconi et al., 2013]. The pattern
of developmental differences observed in individuals
with autism is consistent with difficulties in connecting
objects and spoken words used in language, which
implies a failure to (visually) connect language with the
specific situation/object it is referring to [Brenner et al.,
2007].
Thus, if either the BG that modulates reward based
saccade behavior or if saccade generation itself is chal-
lenged in autism, visual search, visual attention and
gazing toward others would also be disrupted [Mosconi
et al., 2013; Mosconi at al., 2015a; Mosconi, Wang,
Schmitt, Tsai, & Sweeney, ]. Consequently, more com-
plex behaviors like attention, joint attention and shared
engagement will likely be affected and may lead to dif-
ficulties with reading, imitation and social interactions,
among others (Table 1).
Eye-hand coordination.The combined coordina-
tion of eye gaze and hand movement is another essen-
tial elemental skill to interact with people and objects.
This is especially important during the critical develop-
mental periods that are affected in autism [Iverson,
2010]. It has been proposed that the BG could play a
role in synchronizing the visual and motor systems in
visuo-spatial skills specifically for intentional tasks
[Sailer, Eggert, Ditterich, & Straube, 2000]. Experiments
by van Donkelaar and Staub [2000] demonstrated that
temporal coordination between eye and hand are dis-
tinct during two separate conditions: visual versus
remembered targets. Their findings suggest a possible
role for both the BG and the cerebellum as sites where
information relating to visual versus remembered cues
arise that could have distinct temporal substrates and
share some common neural substrates for integration of
eye position information to manual motor responses
[van Donkelaar & Staub, 2000].
Yu and Smith [2013] examined joint attention (par-
ticularly towards goal directed activities with an object
and partner) in neurotypical children and found that
social behavior in one year olds is determined by eye
and hand movements that are tightly coordinated spa-
tially and temporally toward the objects used in the
interaction. Individuals with autism often demonstrate
difficulty acquiring these skills [Yu & Smith, 2013]. Dur-
ing eye-hand coordination tasks, people with autism
took considerably more time to perform movements
that required greater visual-proprioceptive integration
due to altered integration of movement generation
from visual and motor systems [Glazebrook, Gonzalez,
Hansen, & Elliott, 2009]. Furthermore, recent evidence
from performance during pointing and pressing tasks
shows a striking difference in autism when assessed for
eye-hand coordination [Crippa, Forti, Perego, & Mol-
teni, 2013]. These results suggest that individuals with
autism have difficulties synchronizing visual and motor
systems, particularly in processing complex skills.
Some of the sensory and movement differences
observed in autism appear consistent with synchroniza-
tion challenges across cortical and sub-cortical struc-
tures. In turn, this disruption may influence goal-
directed behaviors and action selection. Since the most
basic behaviors such as reaching, opening, feeding one-
self, pointing, handwriting and walking, lead to more
complex behaviors such as following and engaging in
social interactions (play, conversations, games, etc.) as
well academic skills, understanding these underlying
differences in eye-hand coordination will aid in the
development of tasks that are used to practice skills for
effective use of posture, body language, spoken lan-
guage, and alternative means to communicate [Iverson,
2010; Iverson & Fagan, 2013; LeBarton & Iverson, 2016;
Nickel, Thatcher, Keller, Wozniak, & Iverson, 2013;
Northrup, Libertus, & Iverson, 2017]. For example,
teaching coordinated pointing to objects on a
touchscreen or using an augmented alternative commu-
nication device, are widely used by individuals with
autism [Kagohara et al., 2013].
INSAR Subramanian et al./Basal ganglia and autism 7
Movement coordination.Influence on action
through the structure and function of the BG is con-
served throughout vertebrate evolution [Stephenson-
Jones, Samuelsson, Ericsson, Robertson, & Grillner,
2011]. Motor learning involves many brain regions, but
the BG appears to play a key role [Graybiel, 2008].
Hikosaka, Nakamura, Sakai, and Nakahara [2002] sug-
gest that signals originating in the cerebral cortex travel
through BG and cerebellar loop circuits and are opti-
mized based on their reward value and sensorimotor
accuracy. This likely makes it an important feedback
loop for motor skill learning [Hikosaka et al., 2002]. A
review on hierarchical control of goal-directed action in
the cortical-basal ganglia network [Balleine, Dezfouli,
Ito, & Doya, 2015] presents the lines of evidence for
secondary motor areas integrating with the BG to map
actions onto specific outcomes, which allows for adap-
tive choice and goal-directed control. If goal-directed
deliberation between consequences of choosing alterna-
tive actions or action selection is slow and cognitively
demanding, under certain conditions there is a ten-
dency for this decision-making to become habitual and
automatic [Dezfouli & Balleine, 2013]. The root of
repetitive behaviors in autism could be a disruption of
the interplay between goal-directed and habitual learn-
ing processes. This could be a reason why people with
autism have restricted interests, rely on routines and
have difficulties in task switching. Indeed, an MRI study
has correlated increased right caudate volume with
increased repetitive behavior scores in autism [Hol-
lander et al., 2005].
In a comprehensive meta-analysis, Fournier, Hass,
Naik, Lodha, and Cauraugh [2010], reported altered
motor performance in autism compared to typically
developing peers. Significant and large effect size was
found for differences in movement preparation or plan-
ning, upper extremity motor function, gait, and balance
[Fournier et al., 2010]. Specifically, postural control and
mobility were impacted, which are precursors to differ-
ent motor performances, including eye-hand coordina-
tion and inhibition of reflexes [Minshew, Sung, Jones,
& Furman, 2014]. Furthermore, a retrospective analysis
of clinical data found prevalence of hypotonia (reduced
resistance) and apraxia (difficulty in execution) in
autism [Ming, Brimacombe, & Wagner, 2014]. Also,
Torres et al. [2013] objectively separated individuals
with autism from neurotypical individuals by measur-
ing hand trajectories toward a visual stimuli. The study
demonstrated marked differences in hand movements
in individuals with autism and were thus able to divide
the participants into subgroups. They found informa-
tion processed (internal and external) based on the cen-
tral and peripheral nervous system (voluntary and
autonomic) depended on specific task parameters and
coined the term ‘micro-movements,’ which corresponds
to the re-afferent feedback signal that produces stochas-
tic signatures of movement fluctuations over time
[Brincker & Torres, 2013]. These disruptions in move-
ment and their ramifications can impact an individual’s
motor control and, as a consequence, impact their
social interactions and behavioral choices/patterns,
which may be an aspect of the cognitive challenges
that are commonly described in individuals with autism
[Torres et al., 2013].
Concurrent real-time sensory feedback provides bio-
logical systems the ability to adjust actions based on
perception of the body in space (body schema). In the
absence of appropriate feedback, movement is not fluid
nor integrated with other sensory modalities and it
does not take external environmental factors into
account that will allow for the regulation, coordination,
planning, and control of these multiple layers of move-
ment [Crapse & Sommer, 2008; van Beers, 2009]. Feed-
back and feedforward motor control involve subcortical
regions that include the BG [Seidler, Noll, & Thiers,
2004]. In autism, these feedback pathways may not be
clearly defined or differentiated between voluntary or
autonomic, which could impede overall voluntary
movement coordination [Seidler et al., 2004].
Action chaining.Integration of external and inter-
nal information ultimately leads to selection of an
appropriate action. The BG has been proposed to func-
tion as a general-purpose selection mechanism as a
solution to the “selection problem”. This is a funda-
mental computational problem that arises when sen-
sory, cognitive and affective systems composed of
multiple distributed parallel-processing circuits have to
share a limited set of motor resources and is referred to
as “the final common motor path” [Redgrave, Prescott,
& Gurney, 1999]. In a complex motor skill, different
regions of the body and their corresponding muscles
must be coordinated in time. Graybiel [1998] suggested
that the BG mediates motor learning by grouping com-
plex actions into simpler small sequences or behavioral
“chunks”. Although this theory remains controversial,
recent advances to this idea propose that sequence
learning is a result of parallel interacting processes
between the BG, cerebellum and motor cortex depend-
ing on task demands [Graybiel, 1998; Penhune & Steele,
2012].
Among the various elements of motor control, many
individuals with autism have difficulty in the ability to
execute successive motor actions due to the absence of
motor plan integration. The correct execution of central
planning leads to smooth performance of a sequence of
motor actions [Stoit, Van Schie, Slaats-Willemse, & Bui-
telaar, 2013]. This difficulty in carrying out proper
motor plan integration, combined with differences in
saccadic eye movements, smooth pursuit eye move-
ments, and performance (speed, fluency, and accuracy)
8 Subramanian et al./Basal ganglia and autism INSAR
of eye-hand coordinated goal-directed movements can
interfere with efficient motor function, as reviewed in
Torres et al. [2013]. Movement execution challenges
could underlie internal action model prediction errors
that lead to action chaining/motor sequence chal-
lenges. In autism, there is a failure of feedforward pre-
dictions in motor control when executing movement
goals with intact action planning [Stoit et al., 2013].
There is also evidence for feedback difficulty in a bi-
manual load lifting task in autism with a failure of
anticipatory postural adjustments [Schmitz et al., 2003].
Taken together, sensorimotor differences in autism
likely underlie the lack of mastery of body schema, i.e.,
the internal timing, model and representations of the
body in space, that are important for goal-directed
behaviors, action chaining and anticipatory motor
control.
In learning motor tasks and sequences, Haswell and
colleagues (2009), found that people with autism show
a stronger association between internal motor com-
mands and proprioceptive sensory feedback than con-
trols. The authors argue that performance patterns of
motor behaviors of individuals with autism are more
reliant on proprioception. This stronger association cre-
ates difficulties when individuals with autism are chal-
lenged or asked to perform movements represented in
an extrinsic coordinate frame (that uses pre-motor, sup-
plementary motor or posterior parietal cortical repre-
sentations), such as actions based on instructions
(gestures to command) or using common tools (e.g., a
tooth brush). Also, the mechanism of on-line correction
based on movement feedback is challenged in autism
[Haswell, Izawa, Dowell, Mostofsky, & Shadmehr,
2009]. This implies that individuals are often not able
to correct simple movements based on their experiences
[Forti et al., 2011; Northrup et al., 2017]. These differ-
ences may be compensated by various strategies
uniquely employed by individuals with autism, which
leads to variable performance efficiencies and time
delays in goal-oriented actions. Clinically, the altera-
tions in feedback and feedforward mechanisms are
observed as inconsistent performance and accuracy,
beginning with simple tasks and ending into more mul-
tifaceted behaviors [Focaroli, Taffoni, Parsons, Keller, &
Iverson, 2016]. Hence, changes in the external environ-
ment, i.e., extrinsic reference frames, pose a major chal-
lenge to motor performance in autism, especially as it
relates to action chains or motor sequences.
Sensory modulation and processing.The BG has
been described as a region involved in sensorimotor
coordination [Barn
eoud, Descombris, Aubin, & Abrous,
2000; Lynd-Balta & Haber, 1994] and action selection
[Graybiel, 1998; Jin & Costa, 2015], which requires inte-
gration of sensory information. Within the basal gan-
glia, motor learning, planning, initiation, and
execution, as well as decision making and reward
depend on multisensory information processing [Reig &
Silberberg, 2014]. Yin [2010] has reported that lesions
affecting the sensorimotor (dorsolateral) striatum
impaired the acquisition of a simple action sequence.
Therefore, it is likely that alterations in simple sensory
processing could affect complex behaviors including
learning action sequences [Yin, 2010]. The basic func-
tion of integrating sensory information and producing
movements that will lead to appropriate behaviors is
vital to the developing individual. Throughout evolu-
tion, organisms have adapted and responded to their
environment based on the senses they have developed.
Therefore, it is an important avenue of research to
explore consequences for motor output when sensory
processing is altered and leads to avoidance of stimula-
tory environments or activities that involve excessive
sound/noise, different textures, light, visual stimuli,
food avoidance, or even sensory seeking motor activi-
ties (flapping, jumping, etc.).
Adults with autism self-report sensory over-
responsivity for vision, hearing, touch, smell, and taste,
which affects their daily lives and routines [Tavassoli,
Miller, Schoen, Nielsen, & Baron-Cohen, 2014]. A large
study with young children (under 4.5 years old) also
reported altered sensory processing in autism, in partic-
ular, over-reactivity to sound and under-reactivity to
pain [Klintwall et al., 2011]. Additionally, they reported
common sensory traits observed in autism this includes
food selectivity, sound or light sensitivity, sleeping
issues and/or self-stimulating behaviors that correlate
with sensory differences. These findings support the
idea that the presence of sensory processing differences
could be a core underlying characteristic in autism as
well as a crucial factor leading to differences in complex
behaviors and actions [Orefice et al., 2016]. The unique-
ness of the sensory profile in children with autism indi-
cates the need to examine this category as part of the
symptomatology based on its correlation with other
commonly observed core behaviors [Wiggins, Robins,
Bakeman, & Adamson, 2009].
Given the prominence of sensory differences in
autism, discovering the neural circuitry involved would
be an important step toward overcoming the challenges
that confront individuals with autism. Understanding
these sensory and movement challenges will inform
practice of support for individuals with autism to help
them develop better relationships with other people
and moderate reactions to unpleasant external stimuli
they encounter in their surroundings.
Inhibition control.Inhibition control is the ability
to suppress incoming information (both processing and
execution) that interferes with and is extraneous to the
achievement and progress of a current goal [Christ,
Holt, White, & Green, 2007]. The BG participates in
INSAR Subramanian et al./Basal ganglia and autism 9
adaptive control by inhibiting or suppressing inappro-
priate behavior in response to changing circumstances
[For review see Jahanshahi, Obeso, Rothwell, & Obeso,
2015]. The cognitive aspects of inhibition control are
likely a result of interaction of the BG with the prefron-
tal cortex to direct attention away from irrelevant infor-
mation and toward behaviorally relevant information
[Van Schouwenburg, Den Ouden, & Cools, 2015].
Langen et al. [2012] found that people with autism
struggled on go/no-go tasks as compared to controls.
They correlated this performance to altered micro-
structural organization of fronto-striatal white matter in
the putamen tract in autism and related the results to
cognitive models of response inhibition [Langen et al.,
2012]. Although results from studies have been variable,
increased time to inhibit a behavior, longer latency, less
accuracy in a response and susceptibility to interfering
stimuli are characteristics that can disrupt the perfor-
mance of individuals with autism [Christ et al., 2007].
The inability to inhibit incoming visual and auditory
stimuli is also predictive of sensorimotor repetitive
behavioral measures in autism [Mostert-Kerckhoffs,
Staal, Houben, & de Jonge, 2015]. The role of inhibitory
control must be taken into account when assessing and
understanding performance variability on tasks as the
functional level of inhibitory control varies across indi-
viduals within the autism spectrum [Geurts, Begeer, &
Stockmann, 2009]. Understanding inhibitory control is
as important as understanding action control, since
inhibitory control is necessary to achieve fluid coordi-
nated movements in an uncertain stimulatory
environment.
C. Basal Ganglia in Autism: Animal Models of Autism
Several mouse models of autism have been produced
through germ cell genetic engineering or prenatal
chemical exposure [reviews in Chen et al., 2014; Silver-
man, Yang, Lord, & Crawley, 2010]. A few inbreed
mouse strains have also been proposed as models of
autism [Bolivar, Walters, & Phoenix, 2007; McFarlane
et al., 2008; Moy et al., 2009]. Three different criteria
should ideally be fulfilled in order to consider an ani-
mal model relevant to a human clinical condition [Sil-
verman et al., 2010]. These criteria are: (1) construct
validity, which requires that the model reproduces the
same causal factors as those seen in the clinical condi-
tion; (2) face validity, which requires that the model
reproduces the symptoms seen in the disorder; and (3)
predictive validity, which requires that the model con-
sistently responds to pharmacological agents known to
be clinically efficacious. Construct validity is most com-
monly tested in mice by inducing mutations of genes
implicated in autism. Face validity can be tested
through the analysis of behaviors that are deemed
equivalent to autism symptoms [Chen et al., 2014].
However, the relevance to autism of mouse behavioral
studies remains unclear and can be controversial since
some behaviors, such as speech, are uniquely human.
Predictive validity is difficult to test since the clinical
efficacy of current agents for core autism symptoms is
very limited.
A comprehensive set of assays has been used to
assess autism-related behaviors in mice [Crawley, 2012;
Pasciuto et al., 2015; Silverman et al., 2010; W
ohr &
Scattoni, 2013]. These assays address the following core
autism domains: (1) persistent challenges in social com-
munication and interaction across contexts and (2) at
least two of the four following categories of symptoms:
(a) stereotyped or repetitive speech, motor movements
or use of objects; (b) excessive adherence to routines,
ritualized patterns of verbal or nonverbal behavior, or
excessive resistance to change; (c) highly restricted
interests that are unusual in intensity or focus; (d)
hyper- or hypo-reactivity to sensory input or unusual
interest in sensory aspects of the environment. Other
symptoms, notably hyperactivity, cognitive difficulties
and seizures can also be studied in mice. Social and
communication challenges can be assessed by measur-
ing: (1) preferences for other mice versus non-social
objects; (2) mutual social interactions (e.g. sniffing,
physical contact, playing, allo-grooming); (3) social
transmission of food preferences; (4) ultrasonic vocal-
izations and (5) olfactory preferences for social (e.g.,
urine) versus non-social odors. Stereotypies, adherence
to routine and differences in cognitive flexibility can be
assessed through measurements of repetitive behaviors
(e.g., grooming, object burying, digging, jumping), per-
formance in water or dry mazes (e.g., difficulty in
changing strategy to escape a situation or retrieve
food). Excessive adherence to routine/compulsive
behavior can also be tested through measurements of
time spent in a dark or light environment in contextual
fear chambers, in the presence of a familiar versus a
novel object or in the context of nest building. Hyper-
activity, anxiety, and restricted interests can be assessed
by measuring the extent of locomotion, exploratory
behavior and time spent in light or dark areas in an
open field or in an elevated maze. Hyposensitivity to
sensory inputs can be assessed by measuring the extent
of pre-pulse inhibition. The validity of these assays is
supported by evidence that mutations in mice of genes
implicated in autism lead to marked qualitative differ-
ences in several of these behaviors. For example Tuber-
ous sclerosis complex (TSC) is a single gene disorder
associated with core autism symptoms and intellectual
disability. The two genes TSC1 and TSC2 are involved
in the regulation of mRNA translation and mutated or
knockout mice show altered excitability and LTD/LTP
and decreased Purkinje cell numbers in the cerebellum.
10 Subramanian et al./Basal ganglia and autism INSAR
Various social behavior and learning difficulties have
been described as well as increases in compulsive
behavior [Auerbach, Osterweil, & Bear, 2011; Ehninger
et al., 2009; Goorden, Van Woerden, Van Der Weerd,
Cheadle, & Elgersma, 2007; Reith et al., 2013; Tsai
et al., 2012]. Tsai et al. [2012] showed following rapa-
mycin treatment in mutant mice, normal acquisition
and reversal learning behavior along with comparable
social behavior to that of controls in social approach
and social novelty assays. Animal models could thus
serve as potential ways to dissect distinct autism behav-
iors, mechanisms of action and potential treatment
options. Although the TSC model pertains to the cere-
bellum, many single gene disorders associated with
autism symptoms affect the structures of the BG,
including the striatum. Several such genetic models are
described in the following paragraphs.
Shank: The SHANK1,SHANK2, and SHANK3 genes
encode for scaffolding proteins enriched at the post-
synaptic density in glutamatergic synapses [review in
Jiang & Ehlers, 2013]. Mutant mice exhibit major altera-
tions in the organization and function of glutamatergic
synapses in the striatum [Pec¸a et al., 2011] and hippo-
campus [Bozdagi et al., 2010]. Behavioral challenges are
variable and depend on the type of mutation and the
type of targeted SHANK gene [Jiang & Ehlers, 2013].
However, consistent challenges have been reported in
social behaviors and ultrasonic vocalizations. Increased
stereotypies/compulsive behavior and altered cognitive
flexibility have been documented [Bozdagi et al., 2010;
Pec¸a et al., 2011; Schmeisser et al., 2012; Wang et al.,
2011; W
ohr, Roullet, Hung, Sheng, & Crawley, 2011;
Won et al., 2012; Yang et al., 2012]. Adult restoration
of Shank3 in mutant mice has shown plasticity in the
adult brain where social interaction challenges and
repetitive grooming behavior but not anxiety or motor
coordination problems were rescued [Mei et al., 2016].
In consideration of the well-known role of the BG in
stereotypies, these mouse studies provide a strong indi-
cation that altered synaptic plasticity in the BG play a
central role in these behaviors in autism (see also sec-
tion D in this review and the following paragraphs).
Neuroligins: The family (Nlg1; Nlg2 and Nlg3; Nlg4) of
neuroligins, including cell adhesion molecules, has
been implicated in autism and mental retardation.
Mutations in mice have been associated with altered
brain volume and alterations in glutamatergic and/or
GABAergic synapses [Blundell et al., 2010; Jamain et al.,
2008; Radyushkin et al., 2009; Tabuchi et al., 2007].
The behavioral symptoms vary with the type of neuroli-
gin affected but most models reveal social behavior dif-
ficulties. Another study claimed that NL3 mutations
specifically targeting the NAc were necessary and suffi-
cient to increase acquired stereotypical behaviors in
mice, thus identifying specific striatal circuit substrates
and synapses associated with particular behavioral fea-
tures of autism [Rothwell et al., 2014]. In this latter
study, however, it was unclear if the mutation affected
parameters of gait and locomotion versus stereotypical
behaviors.
Engrailed genes:Engrailed 2 (EN2) is linked to autism
and encodes for a homeobox transcription factor
involved in brain pattern formation [Benayed et al.,
2005; Gharani, Benayed, Mancuso, Brzustowicz, & Mill-
onig, 2004; Petit et al., 1995]. EN2
2/2
results in
decreased cell numbers in the cerebellum, hippocam-
pus, and cerebral cortex [Kuemerle, Zanjani, Joyner, &
Herrup, 1997; Sgad
o et al., 2013] and increased seroto-
nin levels in the cerebellum [Cheh et al., 2006]. Hyper-
activity and reduced social play as well as motor,
learning and exploratory differences have been reported
in EN2 deficient mice [Cheh et al., 2006]. Challenges in
reciprocal social interactions, altered fear conditioning
and water maze learning, high immobility in the forced
swim test, reduced prepulse inhibition, mild motor
incoordination and reduced grip strength were also
reported in En2
2/2
mice [Brielmaier et al., 2012]. The
amygdala, which shares specific connections with the
ventral subdivisions of the BG and the ventral striatum,
is also impacted in EN2
2/2
mice [Kuemerle et al., 1997].
This suggests that the ventral “limbic” regions of the
BG may be specifically implicated in the cognitive and
emotional differences in autism.
Other genes: Various alterations have been reported in
mice that harbor mutations in other genes associated
with autism or neurodevelopmental conditions. These
include the Contactin-Associated Protein-Like 2
(CNTNAP2) [Pe~
nagarikano et al., 2011], the Ca
11
-
dependent activator protein for secretion 2 (CADPS2)
[Sadakata et al., 2007]; the voltage–gated sodium chan-
nel type-1 (SCN1A) [Han et al., 2012] which causes
Davet syndrome; the fragile X syndrome gene FMR1
[Irwin, Galvez, & Greenough, 2000; McNaughton et al.,
2008; Mineur, Huynh, & Crusio, 2006; Moy et al.,
2009; Nosyreva et al., 2006; Selby, Zhang, & Sun, 2007;
Spencer, Alekseyenko, Serysheva, Yuva-Paylor, & Paylor,
2005] and the Rett syndrome gene MeCP2 [Chao et al.,
2010; Gemelli et al., 2006; Guy, Hendrich, Holmes,
Martin, & Bird, 2001; Jiang et al., 2013; Moretti, Bouw-
knecht, Teague, Paylor, & Zoghbi, 2005]. The extent
and nature of social and communication challenges
vary widely between various models. The implication of
the BG in some of these models has been documented.
Neuropathology: The major conclusion from animal
studies is that autism involves marked qualitative differ-
ences in synaptic circuitry leading to imbalances in
excitatory/inhibitory neurotransmission, including in
the BG. Furthermore, some findings suggest that pro-
found alterations in GABAergic neurotransmission may
play a central role in autism. For instance, CADPS2 null
INSAR Subramanian et al./Basal ganglia and autism 11
mice have decreased parvalbumin and calbindin cell
numbers respectively in the cortex and cerebellum
[Sadakata et al., 2007]. FMR
1/y
and EN2
2/2
mice have a
loss of parvalbumin in hippocampal and cortical neu-
rons [Selby et al., 2007; Sgad
o et al., 2013]. Mutations
in the neuroligin gene (NL-3 R451C) or prenatal val-
proate result in reduced numbers of parvalbumin-
labeled neurons in the cerebral cortex [Gogolla et al.,
2009]. Loss of MeCP2 in parvalbumin and somatostatin-
expressing GABAergic neurons in the mouse leads to a
Rett syndrome-like phenotype [Ito-Ishida, Ure, Chen,
Swann, & Zoghbi, 2015]. A major question that remains
unanswered is how these developmental imbalances
between inhibition/excitation can contribute to the
constellation of behavioral differences detected in
mouse models. In order to address this question, more
targeted experimental manipulations at the circuit and/
or regional level should be carried out. In this context,
it is of interest that a study including five genetic
mouse models of autism found differences in an asso-
ciative learning task that requires cerebellar plasticity
[Kloth et al., 2015]. On the other hand, loss of the
GABA-synthesizing enzyme Gad67 in striatal neurons is
paralleled by social behavior challenges, hyperactivity
and difficulties in cognitive flexibility [Zhang, Hill,
Labak, Blatt, & Soghomonian, 2014]. These data suggest
that different brain regions could specifically contribute
to different domains of autism symptomatology.
D. Neurobiological Model of Basal Ganglia in Autism
Behaviors
Delay in motor milestones could be the first clinically
observable manifestations of autism that are possibly
rooted in other related and interconnected non-motor
(social–communication–cognition) circuits. These
delays could be due to altered learning, execution, and
performance of motor behaviors. Some of these behav-
iors, specifically delayed motor milestones such as walk-
ing [Ozonoff et al., 2008] and postural control
[Minshew et al., 2014] could likely be the result of alter-
ations within the BG. When children learn to walk,
they begin with an incomplete representation of their
body in space (body schema). With experience, they
gain confidence and motor coordination, and can walk
easily across the room or up a flight of stairs. In a
remarkable manner, after several attempts and falls, the
brain learns to walk and balance [Ehrlich & Schoppik,
2017; Glasauer & Straka, 2017]. Motor commands are
initiated and adjusted dynamically based on internal
and external sensory feedback to maintain gait, bal-
ance, and posture [Emberson, Boldin, Riccio, Guillet, &
Aslin, 2017; Minshew et al., 2014]. After learning this
habit, the skill can be performed automatically. The BG
is involved in the acquisition and the performance of
such learned habits [Graybiel, 2008; Yin & Knowlton,
2006].
A key feature of autism is a tendency toward
restricted and repetitive behaviors [Fung & Hardan,
2014]. The internal reward circuitry in autism that is
associated with restricted and repetitive behavior is
underexplored. One key circuit that likely mediates
repetitive behavior in autism involves the midbrain
dopaminergic nucleus called ventral tegmental area
(VTA) that projects to nucleus accumbens (NAc) in the
ventral part of the striatum (Fig. 1).
The emergence of molecular tools and advances in
genetic engineering have contributed to the develop-
ment of animal models where specific pathways, such
as the neuroligin-3 dependent inhibition onto the
nucleus accumbens (NAC) dopamine type 1 receptor
(D1R) containing neurons in the direct pathway (see
Fig. 2), was shown to be necessary and sufficient to
induce certain repetitive behaviors, including stereo-
typy that was commonly observed in multiple mouse
models of autism [Grueter, Rothwell, & Malenka, 2012;
Rothwell, 2016; Rothwell et al., 2014]. One characteris-
tic of the motor system is the inherent variability in
motor performance that is present when the same
movement is repeated multiple times [Crapse &
Sommer, 2008; van Beers, 2009]. This is guided by the
internal model of our body in space, body schema, cor-
ollary discharge, and sensory feedback mechanisms that
all add to the inherent motor noise that guides motor
learning and performance [van Beers, 2009]. However,
disinhibition of D1R containing medium spiny neurons
in the NAC leads to enhanced motor learning and a ste-
reotypical motor behavior that has almost no variability
in motor reproduction of the task [Rothwell et al.,
2014]. Such stereotypical motor behavior indicates an
absence of extrinsic sensory feedback to the cortex and/
or absence of internal motor noise that is present dur-
ing execution when the same motor command is given
out to the peripheral effectors from the central nervous
system [Brincker & Torres, 2013]. The neuroligin-3
conditional knockout animal models execute this spe-
cific stereotypical behavior [Rothwell et al., 2014] pos-
sibly due to lack of feedback, both external
(environmental) and/or internal (sensory). In the
above example, autism-related behaviors such as ste-
reotypy can be causally attributed to specific synapses
(inhibitory synapses onto D1-receptor containing
medium spiny neurons in the NAC) in specific func-
tional circuits (limbic functional territory, ventral stria-
tum). Various clinically observed autism behaviors (see
Section B), could be described with specificity by
examining the autism BG in detail. Similarly, altered
reward processing in the VTA likely plays a critical
role in restricted and repetitive behaviors that are
observed in obsessive-compulsive disorder (OCD) and
12 Subramanian et al./Basal ganglia and autism INSAR
Figure 1. Basal ganglia (BG) loops - canonical connections (A) Schematic line diagram of the basal ganglia direct, indirect, and hyper-direct pathways with output to the thala-
mus and midbrain dopaminergic projections. (B) The three functional territories of the basal ganglia, which are motor, associative, and cognitive with their corresponding ascend-
ing spiral of connections from midbrain dopaminergic neurons. The ventral to dorsal functional circuits have an ascending spiral of influence. The more dorsal motor circuits are
influenced by the ventral cognitive regions. Modified and redrawn with permission from Haber and Knutson [2010] (C) The cerebral cortical projections onto the BG and the puta-
tive behaviors associated with them in the BG are illustrated. (D) A representative example of one parallel circuit from frontal cortical Area 46 through the BG and cerebellum with
common projections to the cerebellar cortex area Crus II is illustrated. D1R-Dopamine receptor type 1, D2R-Dopamine receptor type 2, GPe-Globus Pallidus externa, GPi-Globus Pal-
lidus interna, STN-Subthalamic Nucleus, GABA- Gamma Aminobutyric Acid, SNpc-Substantia Nigra pars compacta, SNpr-Substantia Nigra pars reticulata, VTA-Ventral Tegmental
Area, NAc-Nucleus Accumbens Shell territory, DN-Dentate Nucleus, PN-Pontine Nucleus
INSAR Subramanian et al./Basal ganglia and autism 13
Figure 2. Basal ganglia (BG) from receptors to cortico-cerebellar loops are demonstrated. (A) Schematic line diagram of the BG anatomical connections between cerebral and cere-
bellar cortex. (B) The ipsilateral and contralateral hemispheric projections of different types of cortical neurons to the BG, thalamus, brainstem and spinal cord. Modified and redrawn
with permission from Shepherd [2013]. (C) Cortico-striatal projection neurons synapsing onto MSNs in the striatum. (D) Magnified excitatory (glutamatergic) axons and inhibitory
(GABAergic) axons synapsing onto MSN dendritic spines, along with likely synaptic cell adhesion molecules, receptors, neurotransmitters and neuromodulators typically found in the
striatum that influence its function. C-Caudate, Pu-Putamen, NAc-Nucleus Accumbens, GPe-Globus Pallidus externa, GPi-Globus Pallidus interna, STN-Subthalamic Nucleus, SNpc-
Substantia Nigra pars compacta, SNpr-Substantia Nigra pars reticulata, VTA-Ventral Tegmental Area, PN-Pontine Nucleus, DN-Dentate Nucleus, PNS-Peripheral Nervous System, IT-CC
Neurons-Intratelencephalic Cortico-cortical Neurons, IT-CStr Neurons-Intratelencephalic Cortico-striatal Neurons, PT Neurons- Pyramidal Tract Neurons, CT Neurons-Cortico-Thalamic
Tract Neurons, D1R-Dopamine receptor type 1, D2R-Dopamine receptor type 2, MSN- Medium Spiny Neurons, 5-HT- 5-Hydroxytryptamine, AcH-AcetylCholine, BDNF-Brain Derived Neu-
rotrophic Factor, Trk B Tyrosine kinase receptor type B, AMPA - a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, NMDA- N-methyl-D-aspartate receptor, mGluR-
metabotropic glutamate receptors, SHANK- SH3 and multiple ankyrin repeat domains 3 (Shank3), also known as proline-rich synapse-associated protein 2 (ProSAP2), GABA-A Ç- Ami-
nobutyric Acid receptor type A, GABA-B Ç- Aminobutyric Acid receptor type B, CNTNAP- Contactin-Associated Protein-Like (CNTNAP)
14 Subramanian et al./Basal ganglia and autism INSAR
in addiction [Rothwell, 2016; Sesack & Grace, 2010;
Wood & Ahmari, 2015]. Taken together with the com-
pelling evidence from imaging studies (See Section A),
animal models (See Section C), and the overlap with
circuits in OCD and addiction [Rothwell, 2016; Wood
& Ahmari, 2015] the NAC-VTA pathway in the BG is
known to play a vital role in restricted and repetitive
behaviors in autism.
The internal organization of the BG provides some
clues to its possible involvement in both motor and
non-motor behaviors like social and communication
challenges in autism. The dorsal striatum of the BG is
involved in motor behaviors and the NAC in the ven-
tral striatum exerts a surprisingly strong influence on
the dorsal striatum (CAU and PUT) (for review, see
[Everitt & Robbins, 2005, 2013, 2016]) by virtue of its
inherent neuroanatomical organization (see Fig. 1b). An
ascending spiral from the dorsal medial tier of midbrain
dopamine neurons, i.e., the VTA, connects it to the
ventral part of the striatum, NAC (see Fig. 1b). The ven-
tral lateral tier of midbrain dopaminergic neurons, i.e.,
the SNpc and the dorsal region of the striatum are
linked together in a progressively spiraling connection
that originates in the midbrain [Fudge & Haber, 2002;
Haber, Fudge, & McFarland, 2000; Haber & Knutson,
2010]. This neuroanatomical organization leads to an
ascending influence from ventral to dorsal regions, i.e.,
the shell territory of the NAC influences the core terri-
tories of NAC and so on. Functionally, this implies that
the limbic domain circuits (located ventrally) exerts a
strong ascending influence on associative striatal func-
tions (located more dorsally) [Cardinal, Pennicott, Suga-
thapala, Robbins, & Everitt, 2001; Christakou, Robbins,
& Everitt, 2004; Di Ciano, Robbins, & Everitt, 2008].
Similarly, the associative striatum in turn ascendingly
influences the dorsally located motor striatum (see Fig.
1b). The ascending spiral of connections from the mid-
brain to the BG implies that the sub-cortical motor cir-
cuit domain does not exercise influence on ventrally
located NAC circuits. Hence, based on just the neuroan-
atomical organization we can conclude that the motor
delays observed in behaviors influenced by BG are likely
due to underlying alterations in the ascending projec-
tions from the reward system, limbic system, and asso-
ciated sub-cortical regions (Fig. 1).
Children at risk for autism or those that receive the
diagnosis of autism often experience motor delays
[Landa, Gross, Stuart, & Faherty, 2013; Ozonoff et al.,
2008; Vernazza-Martin et al., 2005]. These motor
changes are apparent from early postnatal develop-
ment. The behavioral milestone of walking overlaps
best with the age during which regression to autism is
commonly reported [Ozonoff et al., 2008]. There is
increasing evidence that motor challenges are primary
and not secondary to social, communication, and
cognitive skills in autism [Bhat, Galloway, & Landa,
2012; Cummins, Piek, & Dyck, 2005; Fournier et al.,
2010; Landa et al., 2013; Piek, Dawson, Smith, & Gas-
son, 2008]. It has been proposed that changes to the
motor development rate in autism, i.e., slowing in the
second and third year of life, could be possibly due to
an active alteration in both the motor and non-motor
domains of neural circuits [Ozonoff et al., 2008]. Motor
difficulties at this stage of development could be related
to neuronal organization and cortico-sub-cortical neural
circuit development and connectivity. As suggested by
Fournier et al. [2010], this could include fronto-striatal
pathways, BG connections and cerebellar-BG connectiv-
ity, along with other sub-cortical alterations in the BG,
cerebellum and brain-stem. Normal motor skill develop-
ment early in life is an essential foundation for effective
social, emotional, and communication behaviors later
in life (Bhat et al., 2012; Vernazza-Martin et al., 2005).
One area of convergence for these domains resides in
the BG (Fig. 1b), which is accessible to examination
using histological techniques in post-mortem tissue.
Examining the BG opens the possibility of describing a
neurobiological relationship between motor and non-
motor domains in order to gain an overall understand-
ing of their various interactions within a circuit (Fig.
1b) along with its connection to the cerebellum [Mos-
coni et al., 2013, 2015a, ].
There is no single gene, protein or receptor that has
been identified as causative in the etiology of autism.
However, genome wide association studies (GWAS) are
converging on common cellular and molecular targets
that are impacted. Many of these genes are enriched in
pathways regulating cell adhesion (Fig. 2d), guidance of
axons, and guidance of dendrites to appropriate targets
in neuronal circuits during development [Griswold
et al., 2015; Hussman et al., 2011; Wang et al., 2009;
Weiss et al., 2009]. The axon guidance genes could alter
neuronal connectivity in the highly interlinked BG sub-
cortical circuits, thus impacting multiple functional
domains (Fig. 2a). Disruption of cell adhesion genes in
the cortex affects the intratelencephalic and/or pyrami-
dal tract (IT and/or PT) neurons with distinct behavioral
challenges due to their different connectivity patterns
in the cortex and to downstream BG nuclei (Fig. 2c)
[Shepherd, 2013]. Some of these changes could lead to
specific predictions. For example, the cortical inhibitory
circuit alteration in autism [Filice, V
orckel, Sungur,
W
ohr, & Schwaller, 2016; Hashemi, Ariza, Rogers, Noc-
tor, & Mart
ınez-Cerde~
no, 2016] leads to increased excit-
atory output from the cortex to sub-cortical nuclei (Fig.
3b). Compromised neuronal integrity due to altered cell
adhesion molecules could lead to compensatory
changes that alter the excitatory/inhibitory balance in
the synapses of the direct and indirect pathways in the
BG causing altered expression of inhibitory receptors,
INSAR Subramanian et al./Basal ganglia and autism 15
Figure 3. Autism related changes in the BG (A) Striatal synaptic changes contribute to autism-like phenotypes in animal models and genes which affect the function of the
striatum are at a high risk for developing autism. (1) Autism associated Neuroligin-3 (NL3) alterations are recapitulated by conditional deletion of NL3 in the mouse adult ven-
tral striatum, leading to enhanced learning and performance of repetitive behaviors or stereotypy; (2) Shank 3 restoration in the adult mouse is capable of rescuing social inter-
action challenges and repetitive grooming behavior, while incapable of reversing anxiety and motor coordination differences, which possibly changes irreversibly during
development when Shank 3 alterations are present; (3) CNTNAP type 2 is implicated in language learning, development, and neuronal connectivity, especially the associated
cortico-striato-thalamic circuits that connect with prefrontal cortex (higher order cognitive functions) and the language-related association cortex; (4) Neuromodulators such as
dopamine, acetylcholine and serotonin likely have altered receptor expression in the striatum. This could be due to changes in the synaptic structural elements and/or their
related functional changes, such as altered neuronal count and density of cholinergic or parvalbumin positive GABAergic interneurons during development in autism; (5) Neuro-
trophic factors that are developmentally important, such as BDNF and its receptors (Trk), might be impacted in autism leading to altered development and maturation of den-
dritic spines; (6) Inhibitory receptor expression could be increased as a consequence of the altered inhibitory neurotransmission; (7), including possible compensation due to
the prolonged increase in cortical excitatory neurotransmission, which leads to overall excitatory/inhibitory imbalance that is both circuit-specific and connection-specific. (B)
Hypothesized BG circuit changes in autism. Increased cortical excitation to the BG, due to reduced cortical inhibitory neurons, leads to increased excitatory input to the direct,
indirect and hyper-direct pathways. Increased excitation in the hyper-direct pathway leads to increased inhibitory output from the BG to the thalamus. This is aided by the
reduced striatal inhibition from both the direct and indirect pathways (green and red arrows). The increased cortical and STN output to the cerebellar cortex will result in
decreased excitation to the thalamus. Overall, the combined striato-cerebellar pathway alterations likely lead to decreased thalamic feedback to the cortex. Altered PNS sensory
transmission to the cortex could add to the reduced feedback mechanisms in autism, a defining characteristic that leads to altered learning rates and timing. Hence, providing
additional external feedback is critical to improve behaviors in autism. Also, altering neuromodulators in the striatum could break the repetitive cycle of internally rewarding
motor behaviors thus restoring balance in cortico-striato-cerebellar loops.
16 Subramanian et al./Basal ganglia and autism INSAR
neurotransmitters, and neuromodulators (Fig. 3a). Cou-
pled with the likely changes to the axon guidance
genes, these would predict altered long range connec-
tions through recurrent feedback loops within the BG
and cerebellum. Our hypothesis is that all these modifi-
cations in the neuronal circuit would likely lead to sub-
optimal feedback to the cortex (Fig. 3b). Other aspects
of feedback to the cortex are external (environmental)
and internal sensory feedback (body schema). Recent
evidence points to altered peripheral (environmental)
sensory processing even before the information reaches
the central nervous system [Orefice et al., 2016; Torres
et al., 2013]. Also, as discussed in section B, the internal
perception of the position of the body in space (body
schema) is affected in autism. The basis of motor con-
trol theory in understanding the brain is built on this
internal sensory feedback mechanism (also known as
corollary discharge). It is known to involve both the BG
(internal models) and the cerebellum (timing), which
are both implicated in autism [Crapse & Sommer, 2008;
Murray, Lewkowicz, Amedi, & Wallace, 2016; Skefos
et al., 2014; Wegiel et al., 2010; Whitney et al., 2008;
Wolpert, Miall, & Kawato, 1998]. Thus, both the BG
and the cerebellum (subcortical structures, also see sec-
tions A-B) as well as external and internal sensorimotor
feedback are altered and appear to likely produce some
of the complex traits observed in autism.
Summary
Based on the topics presented in this review, the follow-
ing hypotheses may be posited in regard to BG involve-
ment in autism. First, the changes to the BG circuits
could affect the different functional territories of the
BG differently. Second, the E/I balance within these
subcircuits may not reflect the same changes as in cor-
tex (i.e., reduced interneuron number) and/or reduced
inhibitory receptors, as the BG regions have both excit-
atory nuclei and inhibitory nuclei that might be differ-
entially modulated in autism. Third, the impact of the
E/I imbalance in the different nuclei might ultimately
lead to weak feedback to the cortex through the thala-
mus affecting many aspects of motor and non-motor
functions (Fig. 3).
Conclusions and Perspectives
Neuropathological changes observed in autism could
lead to upregulation or downregulation of major inhibi-
tory (GABA
A
and GABA
B
) receptors, excitatory receptors
(AMPA, NMDA, and mGLUR’s), or neuromodulators
(serotonin, dopamine, and acetylcholine) in either cor-
tical, or both cortical and sub-cortical regions. These
neurochemical changes can independently affect local
E/I imbalance in recurrent neural circuits in cerebellum
and BG where minor differences in gene or receptor
expression may lead to more widespread alterations in
motor and non-motor activity throughout these circuits
leading to global behavioral challenges. Normally, the
cerebellum and the BG communicate bi-directionally
through a short di-synaptic pathway. In autism, distur-
bances in these pathway(s) would amplify deleterious
functional effects resulting in modifications in cortical
output and behavior(s). Many autism animal models
successfully replicate some specific aspects of the clini-
cal presentation of autism behaviors through BG
changes. These studies combined with clinical perspec-
tives and neuropathological changes in autism could
guide better design of supports for autism based on the
sensori-motor differences that are rooted in neurobiol-
ogy. Finally, further studies are needed to better delin-
eate subtle changes within the BG circuitry in the
autism brain to elucidate how overlapping frontal, cin-
gulate and motor projections interplay to influence spe-
cific motor actions and cognitive domains that
contribute to many vital aspects of the autism
phenotypes.
CONFLICT OF INTEREST
No authors have a conflict of interest.
Acknowledgments
The authors would like to acknowledge helpful discus-
sions with Dr. Wenjuan Shen and Dr. Shiyong Huang.
This work was supported by NIH Eunice Kennedy
Shriver National Institute of Child Health and Human
Development (NICHD) ARRA 5R01HD039459–06A1
(GJB, P.I.) and Hussman Foundation Grants HIAS15001
and HIAS17001 (GJB, P.I.).
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... The Shank3 ∆c/∆c mice that we have used for our studies are those with C-terminal 508 deletion in the Shank3 gene following a frameshift in exon 21, which includes the homer-binding site in the sterile alpha motif domain. Consequently, there is a partial or total loss of the major naturally occurring isoforms of Shank3 proteins in heterozygotes and homozygotes, respectively [127]. This mutation has a strong construct validity, as it mimics a human mutation, which is not the case for several other Shank3 mutations in mice [127]. ...
... Consequently, there is a partial or total loss of the major naturally occurring isoforms of Shank3 proteins in heterozygotes and homozygotes, respectively [127]. This mutation has a strong construct validity, as it mimics a human mutation, which is not the case for several other Shank3 mutations in mice [127]. In homozygote animals, we reported significant impairments in social novelty preference, stereotyped behavior and gait. ...
Article
Full-text available
Autism spectrum disorders (ASD) are complex conditions that stem from a combination of genetic, epigenetic and environmental influences during early pre- and postnatal childhood. The review focuses on the cerebellum and the striatum, two structures involved in motor, sensory, cognitive and social functions altered in ASD. We summarize clinical and fundamental studies highlighting the importance of these two structures in ASD. We further discuss the relation between cellular and molecular alterations with the observed behavior at the social, cognitive, motor and gait levels. Functional correlates regarding neuronal activity are also detailed wherever possible, and sexual dimorphism is explored pointing to the need to apprehend ASD in both sexes, as findings can be dramatically different at both quantitative and qualitative levels. The review focuses also on a set of three recent papers from our laboratory where we explored motor and gait function in various genetic and environmental ASD animal models. We report that motor and gait behaviors can constitute an early and quantitative window to the disease, as they often correlate with the severity of social impairments and loss of cerebellar Purkinje cells. The review ends with suggestions as to the main obstacles that need to be surpassed before an appropriate management of the disease can be proposed.
... ; https://doi.org/10.1101/2020.09.28.316828 doi: bioRxiv preprint associated with one specific brain structure. Indeed, both the basal ganglia and the cerebellum display functional and anatomical abnormalities in autism spectrum disorders (Gowen & Miall, 2005;Fatemi et al., 2012;Subramanian et al., 2017). ...
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Autism is a developmental disorder characterized by impaired social skills and accompanied by motor and perceptual atypicalities. Its etiology is an open question, partly due to the diverse range of associated difficulties. Based on recent observations that individuals with autism are slow in updating perceptual priors, we now hypothesized that motor updating is also slow. Slow motor updating is expected to hamper the ability to synchronize to external events, since asynchronies are corrected sluggishly. Since sensorimotor synchronization is important for social bonding and cooperation, its impairment is expected to impair social skills. To test this hypothesis, we measured paced finger tapping to a metronome in neurotypical, ASD, and dyslexia groups. Dyslexia was assessed as a control group with a non-social neurodevelopmental atypicality. Only the ASD group showed reduced sensorimotor synchronization. Trial-by-trial computational modelling revealed that their ability to form controlled motor responses and to maintain reliable temporal representations was adequate. Only their rate of error-correction was slow and was correlated with the severity of their social difficulties. Taken together, these findings suggest that slow updating in autism contributes to both sloppy sensorimotor performance and difficulties in forming social bonds. Significance The prevalence of autism diagnosis has increased immensely is the last decades. Yet its etiology remains a challenge, partly since the functional relations between characteristic social difficulties, perceptual and motor atypicalities are not understood. Using trial-by-trial computational modelling, we show that a single deficit underlies the poor synchronization of individuals with autism in both static and changing environments. Slow updating, leading to slow online error correction of motor plans, has an immense explanatory power explaining both difficulties in sensorimotor synchronization, and social impairments.
... Although attention is usually focused on the differences in complex behaviors of social communication, there is a large body of research that implicates alterations in fundamental motor patterns in ASD. Basic motor differences during development may translate into challenges with complex behaviors that rely on the acquisition of fundamental motor skills (for review, see: Subramanian et al., 2017). The underlying circuitry within the brain that is responsible for mediating such a diverse set of motor and cognitive behaviors has not been fully defined, however, there is growing consensus that the cerebellum plays a major role in ASD (Fatemi et al., 2012;Becker and Stoodley, 2013;Rogers et al., 2013;Wang et al., 2014;Hampson and Blatt, 2015). ...
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At present, the neuronal mechanisms underlying the diagnosis of autism spectrum disorder (ASD) have not been established. However, studies from human postmortem ASD brains have consistently revealed disruptions in cerebellar circuitry, specifically reductions in Purkinje cell (PC) number and size. Alterations in cerebellar circuitry would have important implications for information processing within the cerebellum and affect a wide range of human motor and non-motor behaviors. Laser capture microdissection was performed to obtain pure PC populations from a cohort of postmortem control and ASD cases and transcriptional profiles were compared. The 427 differentially expressed genes were enriched for gene ontology biological processes related to developmental organization/connectivity, extracellular matrix organization, calcium ion response, immune function and PC signaling alterations. Given the complexity of PCs and their far-ranging roles in response to sensory stimuli and motor function regulation, understanding transcriptional differences in this subset of cerebellar cells in ASD may inform on convergent pathways that impact neuronal function.
... [3,4,8,38]. Studies have also demonstrated that approaches that activate motor planning, execution, and coordination can positively impact the disrupting information flow and the cluster of atypical behavioral characteristics [14,16,17,[39][40][41][42][43][44]. To this end, the expressive functions of the body through dance may act directly on communication since they can influence the process of social interaction by transmitting inner feelings to the external environment [24,38]. ...
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Objective This study addressed dance practice intertwining communication, functional independence and social behavior in autistic children and adolescents with all levels of need support. Design A pilot randomized clinical trial with seventy-two participants between 8 and 15 years old were assessed for eligibility. Setting Theater rehearsal room and mental health clinic. Interventions Dance group (n = 17) or control group (n = 19), 24 sessions, once a week, lasting 40 min. Main outcome measures The Autism Behavior Checklist (ABC), Autistic Screening Questionnaire (ASQ), Childhood Autism Rate Scale (CARS), Functional Independence Measure (FIM), and World Health Organization Disability Assessment Schedule (WHODAS, version 2.0, to assess mothers’ functioning) were applied at two time points: baseline and end-point. Results Differences between dance and control groups were significant at post-intervention for communication (mean difference: 1.31; 99.8%CI: 0.29, 2.32, p < 0.001, d = 0.93); social cognition (mean difference: 1.01; 99.8%CI: 0.13, 1.89, p < 0.001, d = 0.82); autistic behavior (mean difference: 11.82; 99.8%CI: 17.33, −6.31, p < 0.001, d = 1.45). Conclusions In this preliminary study, the findings provide ways of communication and social interaction through dance practice by autistic children and adolescents with all levels of support needs. Research on neurodiversity is needed to understand its feasibility and the lifestyle appropriation.
... For example, difficulties with social skills may arise in part due to affective cues (e.g., an emotional facial expression) that cannot be properly incorporated as feedback signals into an internal model to build predictions and guide the formation of appropriate habitual social responses. Additionally, the repetitive behaviors and preference for routines observed in ASD may reflect altered reward circuitry (Fatemi et al. 2012;Gotham et al. 2013;Subramanian et al. 2017), from which the cerebellum receives input for learning and adjusting behaviors. Nonetheless, the array of ASD symptoms involves numerous mental processes governed by multiple brain regions (such as the basal ganglia) and the precise contribution of the cerebellum has yet to be determined. ...
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There is growing evidence of the cerebellum’s contribution to emotion processing from neuroimaging studies of healthy function and clinical studies of cerebellar patients. As demonstrated initially in the motor domain, one of the cerebellum’s functions is to construct internal models of an individual’s state and make predictions about how future behaviors will impact that state. By utilizing widespread connections with neocortex and subcortical regions such as the basal ganglia, the cerebellum can monitor and modulate precisely timed patterns of events using prediction and reward-based error feedback in a diverse range of tasks including auditory emotion prosody recognition. In coordination with a broader affective network, the cerebellum helps to select and refine emotional responses that are the most rewarded in a particular context, strengthening neural activity in relevant regions to form a representational chunk. This chunked set of affective stimuli, cognitive evaluations, and physiological responses subsequently can be enacted as a unitary response (i.e., an emotional habit) more quickly and with less attentional control than for a novel stimulus or goal-oriented action. Such emotional habits can allow for efficient, automatic, stimulus-triggered responses while maintaining the flexibility to adapt output when prediction errors signal a renewed need for cerebellar modification of cortical activity, or, conversely, may lead to behavioral or mood disorders when habitual responses persist despite negative consequences.
... Since the basal ganglia in general has been reported to have volume differences (for review: Subramanian et al., 2017) and receptor differences (Brandenburg et al., 2020) in FIGURE 3 | (A) Autism spectrum disorder cases were separated into groups based on medical reports of seizure occurrence. In the globus pallidus (GP), all seven seizure cases had a diagnosis of epilepsy. ...
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Genetic variance in autism spectrum disorder (ASD) is often associated with mechanisms that broadly fall into the category of neuroplasticity. Parvalbumin positive neurons and their surrounding perineuronal nets (PNNs) are important factors in critical period plasticity and have both been implicated in ASD. PNNs are found in high density within output structures of the cerebellum and basal ganglia, two regions that are densely connected to many other brain areas and have the potential to participate in the diverse array of symptoms present in an ASD diagnosis. The dentate nucleus (DN) and globus pallidus (GP) were therefore assessed for differences in PNN expression in human postmortem ASD brain tissue. While Purkinje cell loss is a consistent neuropathological finding in ASD, in this cohort, the Purkinje cell targets within the DN did not show differences in number of cells with or without a PNN. However, the density of parvalbumin positive neurons with a PNN were significantly reduced in the GP internus and externus of ASD cases, which was not dependent on seizure status. It is unclear whether these alterations manifest during development or are a consequence of activity-dependent mechanisms that lead to altered network dynamics later in life.
... As far as we know, mitochondrial dysfunction plays an important part in the etiology of diseases of the basal ganglia [41][42][43]. Basal ganglia disorders are associated with motor, social and communication difficulties that are similar to those associated with autism [44]; therefore, lactate and creatine measurements in MRS from the basal ganglia could help evaluate the treatments for mitochondrial dysfunction caused by PPA when used to create an autism model. There is growing evidence of a strong relation between central gliosis and ASD [45]. ...
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Background Autism is a clinically defined neurodevelopmental disorder with unknown origin characterized by significant social, communication and behavioral challenges. Although it can be a lifelong condition, treatments can help alleviate symptoms and enhance a patient's quality of life. Purpose We aimed to assess the therapeutic potential of finasteride in autism with biochemical markers, histopathological evaluation, behavioral tests and radiological imaging. Materials and Methods Propionic acid (PPA) was injected intraperitoneally into 20 out of 30 rats for 5 days to establish an autism model. Rats were randomly assigned into four groups: control group (no procedure was applied, n=10), placebo group (intraperitoneal PPA + 1 ml/kg/day % 0.9 NaCl saline was given via oral gavage for 15 days, n=10) and treated group (intraperitoneal PPA + 5 mg/kg/day of finasteride was given via oral gavage for 15 days, n=10). After 4 days of behavioral tests, magnetic resonance spectroscopy (MRS) was performed for measuring creatine and lactate levels. All animals were sacrificed for histopathological examination and biochemical analysis of brain tissue. Results MDA, NFκB, TNF-α, IL-2, IL-17A and lactate levels in brain homogenates were significantly increased in the placebo group compared to the control group, while Nfr2 levels were decreased; and the levels of all biochemical markers were reversed by finasteride treatment. A significant improvement was observed in autism-like behaviors in rats treated with finasteride compared to the placebo group. Further, the creatine and lactate levels in corpus striatum in MRS, the neuronal counts and glial activity of the hippocampus and cerebellum were closer to the control group in the finasteride-treated group compared to the placebo group. Conclusion Finasteride led significant improvement in autism-like symptoms with its antioxidant effect through Nrf2 modulation in addition to its anti androgen effect.
... The combination of learning systems based on the basal ganglia and cerebellum allows for more stable and faster learning of goal-directed behavior than individual systems (Dasgupta et al., 2014). The imbalance between the two systems may lead to aberrant motor and non-motor functions (Subramanian et al., 2017). Based on these studies, the interaction between the cerebellum and basal ganglia may play an important role in RRBs. ...
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Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by deficits in social communication, social interaction, and repetitive restricted behaviors (RRBs). It is usually detected in early childhood. RRBs are behavioral patterns characterized by repetition, inflexibility, invariance, inappropriateness, and frequent lack of obvious function or specific purpose. To date, the classification of RRBs is contentious. Understanding the potential mechanisms of RRBs in children with ASD, such as neural connectivity disorders and abnormal immune functions, will contribute to finding new therapeutic targets. Although behavioral intervention remains the most effective and safe strategy for RRBs treatment, some promising drugs and new treatment options (e.g., supplementary and cell therapy) have shown positive effects on RRBs in recent studies. In this review, we summarize the latest advances of RRBs from mechanistic to therapeutic approaches and propose potential future directions in research on RRBs.
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