The developmental neurobiology of autism spectrum disorder.
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ABSTRACT: Impaired responsivity to hypercapnia or hypoxia is commonly considered a mechanism of failure in sudden infant death syndrome (SIDS). The search for deficient brain structures mediating flawed chemosensitivity typically focuses on medullary regions; however, a network that includes Purkinje cells of the cerebellar cortex and its associated cerebellar nuclei also helps mediate responses to carbon dioxide (CO2) and oxygen (O2) challenges and assists integration of cardiovascular and respiratory interactions. Although cerebellar nuclei contributions to chemoreceptor challenges in adult models are well described, Purkinje cell roles in developing models are unclear. We used a model of developmental cerebellar Purkinje cell loss to determine if such loss influenced compensatory ventilatory responses to hypercapnic and hypoxic challenges. Twenty-four Lurcher mutant mice and wild-type controls were sequentially exposed to 2 % increases in CO2 (0-8 %) or 2 % reductions in O2 (21-13 %) over 4 min, with return to room air (21 % O2/79 % N2/0 % CO2) between each exposure. Whole body plethysmography was used to continuously monitor tidal volume (TV) and breath frequency (f). Increased f to hypercapnia was significantly lower in mutants, slower to initiate, and markedly lower in compensatory periods, except for very high (8 %) CO2 levels. The magnitude of TV changes to increasing CO2 appeared smaller in mutants but only approached significance. Smaller but significant differences emerged in response to hypoxia, with mutants showing smaller TV when initially exposed to reduced O2 and lower f following exposure to 17 % O2. Since cerebellar neuropathology appears in SIDS victims, developmental cerebellar neuropathology may contribute to SIDS vulnerability.The Cerebellum 08/2014; · 2.86 Impact Factor
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ABSTRACT: IntroductionA total of 38 brain cytoarchitectonic subdivisions, representing subcortical and cortical structures, cerebellum, and brainstem, were examined in 4- to 60-year-old subjects diagnosed with autism and control subjects (a) to detect a global pattern of developmental abnormalities and (b) to establish whether the function of developmentally modified structures matches the behavioral alterations that are diagnostic for autism. The volume of cytoarchitectonic subdivisions, neuronal numerical density, and total number of neurons per region of interest were determined in 14 subjects with autism and 14 age-matched controls by using unbiased stereological methods.ResultsThe study revealed that significant differences between the group of subjects with autism and control groups are limited to a few brain regions, including the cerebellum and some striatum and amygdala subdivisions. In the group of individuals with autism, the total number and numerical density of Purkinje cells in the cerebellum were reduced by 25% and 24%, respectively. In the amygdala, significant reduction of neuronal density was limited to the lateral nucleus (by 12%). Another sign of the topographic selectivity of developmental alterations in the brain of individuals with autism was an increase in the volumes of the caudate nucleus and nucleus accumbens by 22% and 34%, respectively, and the reduced numerical density of neurons in the nucleus accumbens and putamen by 15% and 13%, respectively.Conclusions The observed pattern of developmental alterations in the cerebellum, amygdala and striatum is consistent with the results of magnetic resonance imaging studies and their clinical correlations, and of some morphometric studies that indicate that detected abnormalities may contribute to the social and communication deficits, and repetitive and stereotypical behaviors observed in individuals with autism.Acta neuropathologica communications. 09/2014; 2(1):141.
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ABSTRACT: IntroductionCharacterization of the type and topography of structural changes and their alterations throughout the lifespan of individuals with autism is essential for understanding the mechanisms contributing to the autistic phenotype. The aim of this stereological study of neurons in 16 brain structures of 14 autistic and 14 control subjects from 4 to 64 years of age was to establish the course of neuronal nuclear and cytoplasmic volume changes throughout the lifespan of individuals with autism.ResultsOur data indicate that a deficit of neuronal soma volume in children with autism is associated with deficits in the volume of the neuronal nucleus and cytoplasm. The significant deficits of neuronal nuclear and cytoplasmic volumes in 13 of 16 examined subcortical structures, archicortex, cerebellum, and brainstem in 4- to 8-year-old autistic children suggest a global nature of brain developmental abnormalities, but with region-specific differences in the severity of neuronal pathology. The observed increase in nuclear volumes in 8 of 16 structures in the autistic teenagers/young adults and decrease in nuclear volumes in 14 of 16 regions in the age-matched control subjects reveal opposite trajectories throughout the lifespan. The deficit in neuronal nuclear volumes, ranging from 7% to 42% in the 16 examined regions in children with autism, and in neuronal cytoplasmic volumes from 1% to 31%, as well as the broader range of interindividual differences for the nuclear than the cytoplasmic volume deficits, suggest a partial distinction between nuclear and cytoplasmic pathology.Conclusions The most severe deficit of both neuronal nucleus and cytoplasm volume in 4-to 8-year-old autistic children appears to be a reflection of early developmental alterations that may have a major contribution to the autistic phenotype. The broad range of functions of the affected structures implies that their developmental and age-associated abnormalities contribute not only to the diagnostic features of autism but also to the broad spectrum of clinical alterations associated with autism. Lack of clinical improvement in autistic teenagers and adults indicates that the observed increase in neuron nucleus and cytoplasm volume close to control level does not normalize brain function.Acta neuropathologica communications. 01/2015; 3(1):2.
Editor’s Note: Two reviews in this week’s issue examine the rapidly expanding interest in autism research in the neuroscience
community. Moldin et al. provide a brief prospective on the overall state of research in autism. DiCicco-Bloom and colleagues
summarize their presentations at the Neurobiology of Disease workshop at the 2005 Annual Meeting of the Society for
Key words: cerebellum; autism; behavior; cognitive; brain development; imaging; mice; fMRI; genetics; Purkinje neurons; human fore-
The autism spectrum disorder (ASD) is among the most devas-
tating disorders of childhood in terms of prevalence, morbidity,
outcome, impact on the family, and cost to society. According to
an emotional disturbance resulting from early attachment expe-
riences (Bettelheim, 1967), ASD is now recognized as a disorder
of prenatal and postnatal brain development. Although ASD is
primarily a genetic disorder involving multiple genes, insights
into underlying mechanisms will require a multidisciplinary ap-
proach. Assessment of the earliest clinical signs and symptoms
neuropathology can be used to identify the underlying brain re-
gions, neural networks, and cellular systems. In turn, the efforts
of human and animal geneticists and neuroscientists are needed
to define molecular and protein signaling pathways that mediate
normal as well as abnormal development of language, social in-
teraction, and cognitive and motor routines. In this review, we
focus on several issues: the earliest manifestations of ASD, re-
ported abnormalities of brain growth, functional neural net-
works, and neuropathology. We also consider the possible etio-
logical factors and the challenges of creating animal models for
this uniquely human behavioral disorder.
social behaviors and interactions. These deficits prevent the de-
velopment of normal interpersonal relationships of affected pa-
tients with their parents, siblings, and other children. Deficits in
nonverbal communication include reduced eye contact, facial
expression, and body gestures (American Psychiatric Associa-
tion, 1994). These disorders include prototypic autistic disorder,
Asperger syndrome, and pervasive developmental disorder–not
symptom domains: deficits in communication, abnormal social
iors. Autistic disorder is typically noticed in the first or second
year of life. The manifestations include delay or abnormality in
language and play, repetitive behaviors, such as spinning things
or lining up small objects, or unusual interests such as preoccu-
pations with stop signs or ceiling fans. Asperger syndrome also
involves social symptoms but language development and non-
Alliance for Autism Research (www.autismspeaks.org), and the New Jersey Governor’s Council on Autism. This
Programs, Society for Neuroscience. We thank Dr. James H. Millonig for insightful critical review and Dr. Gary
Robert Wood Johnson Medical School, 675 Hoes Lane, RWJSPH Room 362, Piscataway, NJ 08854. E-mail:
TheJournalofNeuroscience,June28,2006 • 26(26):6897–6906 • 6897
verbal intelligence are nearly normal. Asperger syndrome, how-
ical autism) differs from autistic disorder by the absence of
subtle deficits in all three core symptom domains. In the past,
more than half of children with autistic disorder had nonverbal
their nonverbal skills typically exceeded their verbal perfor-
may no longer be the case, perhaps because of better identifica-
tion of mild cases, the effects of earlier and more effective special
education interventions, and/or more accurate assessment of
nonverbal intelligence in children with limited social motivation
(Chakrabarti and Fombonne, 2001). Because these three disor-
ders frequently occur within the same family, they may not be
genetically distinct (Lord and Bailey, 2002).
There is marked phenotypic diversity in ASD, with impair-
ment in each symptom domain varying greatly between individ-
uals. In addition, there may be several distinct phenotypic pro-
files. For example, social development and repetitive behaviors
follow different timelines, with social deficits often improving
during preschool years, whereas repetitive behaviors become
more obvious. Approximately 25–35% of children develop a few
spontaneous words and early social routines (e.g., playing peek-
a-boo) at ?1 year of age, reach a plateau for several months, and
then gradually lose the skills altogether. Those with this regres-
sion may regain the skills months later [or sometimes not at all
(Luyster et al., 2005)]. Another 25% of children develop seizures
2 years, as well as adults using a combination of standardized
instruments: a parent interview (e.g., the Autism Diagnostic In-
terview–Revised) and an observational scale (e.g., the Autism
Diagnostic Observation Schedule). These instruments are cur-
rently the most reliable, sensitive, and specific tools for research.
Although these instruments are now being used as metrics for
ASD severity, caution is required because specific group norms
have not been defined for different age groups or distinct intel-
identified before 2 years of age. The earliest signs recognized in
infancy (?1 year) or toddlers are nonspecific (e.g., irritability,
in language, including babbling and response to speech, and in
social engagement. By 3 years of age, difficulties in the three ma-
jor domains (social reciprocity, communication, and restricted/
repetitive interests) are typically observed. ASD is easiest to dif-
and language impairments, in late preschool and early school
years. Thereafter, the consequences of compensatory strategies
Because early developmental interventions may significantly
alter ASD outcomes, diagnostic instruments that are effective
are focusing on the early behavioral signs that previously were
as many as 50% of parents recall abnormalities during the first
year, including extremes of temperament and behavior (from
marked irritability to alarming passivity), poor eye contact, and
lack of response to parental voices or interaction. Home videos
reveal similar developmental differences by 12 months of age.
possibly biased sampling and leave uncertainty about the onset
and progression of early signs. To address these limitations, in-
vestigators have turned to prospective studies of infants at high
risk for ASD. Siblings born to families with an ASD child have a
50- to 100-fold greater chance of ASD, with a recurrence rate of
5–8% (Szatmari et al., 1998). These longitudinal studies offer
several methodological advantages, including the use of stan-
dardized conditions with a priori selection of time points and
measures based on specific hypotheses (Zwaigenbaum et al.,
imitation, social responses (orienting to name, anticipatory re-
sponses, eye contact, reciprocal smiling), motor control, and re-
activity (Zwaigenbaum et al., 2005). There is also evidence of
reported that 4-month-old ASD siblings show decreased syn-
chrony during infant-led interactions with their mothers, sug-
gesting that subtle social abnormalities may precede more obvi-
communicative, and cognitive functions are a starting point to
look for evidence of abnormal brain growth, development, and
function by clinical imaging and neuropathological studies.
early deficitsin social,
and neuropathological techniques have revealed macroscopic
and microscopic abnormalities of development.
Morphometric and chemical neuroimaging studies
During early childhood, brain volume in ASD shows abnormal
enlargement, but these differences diminish somewhat by later
childhood or adolescence. This pattern has been detected only
recently because for much of its 70 year history, ASD brain ab-
normalities were viewed as static. Thus, the possibility of age-
the older child, adolescent, or adult (Cody et al., 2002), rarely
investigating the young, developing brain (Courchesne et al.,
2001, 2004; Sparks et al., 2002; Hazlett et al., 2005). The few
complex pattern of growth abnormalities in the cerebellum, ce-
rebrum, and amygdala and possible differences in hippocampus
(Hashimoto et al., 1995; Courchesne et al., 2001; Aylward et al.,
2002; Carper et al., 2002; Sparks et al., 2002; Herbert et al., 2004;
Schumann et al., 2004; Carper and Courchesne, 2005; Hazlett et
al., 2005). Age-related differences in specific brain region growth
were also apparent in a meta-analysis (Redcay and Courchesne,
Brain size has been defined using head circumference, a reli-
able indicator of volume especially during early childhood; volu-
metric calculations using magnetic resonance imaging (MRI);
and postmortem brain weights. At birth, the average head cir-
cumferencein ASD patients
(Courchesne and Pierce, 2005a). However, by 3–4 years of age,
brain size in ASD exceeds normal average by ?10% based on in
and MRI morphometry (Courchesne et al., 2001; Sparks et al.,
2002; Redcay and Courchesne, 2005). A recent brain volume
study using a larger toddler sample (51 children; 18–35 months
6898 • J.Neurosci.,June28,2006 • 26(26):6897–6906DiCicco-Bloometal.•Mini-Review
2005). By 6–7 years of age, brain size in ASD may exhibit only a
small increase (Courchesne et al., 2001; Sparks et al., 2002; Red-
cay and Courchesne, 2005; Carper et al., 2006). However, forth-
coming data from the largest study reveals a persistent ?5% dif-
ference at older ages (Schultz et al., 2005a), consistent with
extensive head circumference data in older patients. Thus, all
emerging data indicate that there is a brain growth phenotype in
al., 2002; Hazlett et al., 2005), especially white matter immedi-
ately underlying the cortex (Herbert et al., 2004). There is also
increased cerebellar white and gray matter (Courchesne et al.,
2001), although this finding may vary with sample selection and
methodology (Hazlett et al., 2005). In contrast, the cerebellar
vermis, which is predominantly gray matter, is reduced in size
regional concentrations of neuron-related molecules such as
N-acetyl aspartate, creatine, and myoinositol. Given the brain
enlargement in ASD, one might have predicted increases in neu-
ronal markers attributable to enhanced neuronal or synaptic
density. However, these markers were all decreased in 3- to
4-year-old children with ASD (Friedman et al., 2003). The com-
bination of altered molecular markers and an increase in white
and gray matter could reflect changes in (1) the numbers and
sizes of neurons and glia; (2) the elaboration of axons, dendrites
and synapses; (3) axodendritic pruning; (4) programmed cell
inflammatory response has also been described in frontal cortex
and cerebellar regions, including cytokine production and acti-
vation of microglia and astrocytes (Courchesne and Pierce,
2005b; Vargas et al., 2005).
in ASD. Classical studies have focused primarily on autistic dis-
case reports), use of possibly biased quantification methods, and
the presence of comorbid mental retardation and/or epilepsy
(Palmen et al., 2004). Nevertheless, these studies revealed abnor-
malities in brain development. Approximately 20% of the cases
exhibit macrocephaly (head circumference ?97th percentile), a
finding already noted in some children in the first report on
autistic disorder (Kanner, 1943). Microscopically, the following
consistent findings have been identified: decreased numbers of
cerebellar Purkinje cells [21 of 29 cases in 8 studies, 22 of 24 with
MR and 11 of 24 with epilepsy (Williams et al., 1980; Ritvo et al.,
1986; Fehlow et al., 1993; Kemper and Bauman, 1993; Guerin et
al., 1996; Bailey et al., 1998; Fatemi et al., 2002; Lee et al., 2002)],
age-related changes in cerebellar nuclei and inferior olive [5 of 5
1991)], brainstem and olivary dysplasia [4 of 6 cases in 2 studies,
al., 1998)], alterations in the neocortex, such as misoriented py-
8 of 15 with epilepsy (Coleman et al., 1985; Hof et al., 1991;
Kemper and Bauman, 1993; Guerin et al., 1996; Bailey et al.,
1998)], signs of cortical dysgenesis [30 of 32 cases in 6 studies, 16
of 22 with MR and 8 of 15 with epilepsy (Bailey et al., 1998;
Fatemi, 2001; Fatemi and Halt, 2001; Casanova et al., 2002a,b;
Araghi-Niknam and Fatemi, 2003)], and increased cell packing
Bauman, 1993; Guerin et al., 1996; Raymond et al., 1996)]. The
are decreased cerebellar Purkinje neurons and cerebral cortex
dysgenesis. Data on the limbic system and age-related hindbrain
changes lack independent laboratory replication. These findings
may represent alterations in primary developmental processes
such as precursor proliferation, programmed cell death, neuron
migration, axodendritic outgrowth, synaptogenesis, and prun-
ing, although the pathological consequences of epilepsy and its
treatment must also be considered.
By themselves the microscopic changes do not explain mac-
rocephaly nor evidence of an enlarged brain in neuroimaging
studies (Cody et al., 2002; Palmen and van Engeland, 2004;
ies included brains from the first years of life when the age-
dependent enlargement has been most clearly characterized
(Courchesne et al., 2001; Sparks et al., 2002; Hazlett et al., 2005;
number in six subjects with ASD (12.3 ? 3.4 years of age; mean
age ? SEM; MR, 6 of 6; epilepsy, 3 of 6) compared with six
age-matched controls (12.8 ? 3.8 years of age) (C. Schmitz, un-
published observations). ASD subjects also exhibit an ?5% re-
S1 [area 3b of Vogt and Vogt (1919)] (C. Schmitz and M.
Casanova, unpublished observations). The latter results support
previous findings of changes in minicolumnar organization in
other cortical regions in ASD (Casanova et al., 2002a). A reduc-
tion in minicolumn width could reflect changes in GABAergic
systems (Blatt et al., 2001; Schmitz et al., 2005) that may alter
lateral inhibition (Gustafsson, 1997; Bertone et al., 2005) or un-
derlie excess local cerebral connectivity at the expense of long-
distance connectivity (Courchesne and Pierce, 2005b). Other
composition of nicotinic receptors (Lee et al., 2002; Martin-Ruiz
et al., 2004; Mukaetova-Ladinska et al., 2004).
Functional neuroimaging studies
bances that normally map onto specific brain networks, func-
tional MRI (fMRI) can be useful to examine the neural systems
affected in ASD. The three core symptom domains likely involve
widely dispersed neural systems, perhaps implying a generalized
that not all brain systems are equally affected. Although ASD
alters language, attention, communication, and social interac-
(Schultz and Robins, 2005). The earliest fMRI work focused on
social perception, such as person recognition through the face
(Schultz et al., 2000). More recent work has examined the per-
ception of facial expression, joint attention, empathy, and social
cognition (Fig. 1). These studies indicate that the skill deficits of
ASD are accompanied by reduced neural activity in regions that
normally govern the specific functional domain. For example,
deficits in joint attention are associated with reduced activity in
the posterior superior temporal sulcus (Pelphrey et al., 2005),
whereas deficits in social perception and/or emotional engage-
ment and arousal are associated with reduced activity in the
DiCicco-Bloometal.•Mini-Review J.Neurosci.,June28,2006 • 26(26):6897–6906 • 6899
rons (i.e., motor neurons that fire when the animal or person
watches the actions of others) might be involved in deficits in
empathy (Dapretto et al., 2006), whereas positron emission to-
mography studies showed medial prefrontal and amygdaloid
one else’s perspective) (Castelli et al., 2002).
Although the deficits in ASD are undoubtedly widely distrib-
uted, the best replicated fMRI abnormality is hypoactivation of
the fusiform face area (FFA) (Schultz, 2005). Individuals with
al., 2002). Although nearly all fMRI studies report FFA hypoac-
tivation, its meaning depends greatly on the psychological task
and the correlation with other behavioral measures. In normal
subjects, tasks that require the participant to individuate specific
faces show much more FFA activation than tasks that only re-
quire basic level “person detection.” The latter task might be
engaged by passive viewing (Grill-Spector et al., 2004). Because
individuals with ASD do not have deficits in detecting people
versus other objects, it is not unexpected that there are smaller
group differences with passive viewing of faces. It will be impor-
tant that future studies use fMRI tasks that drive the social brain
ities. For example, Dalton et al. (2005) found that individual
differences in FFA hypoactivation correlated inversely with the
time the participant spent fixating visually on the subject’s eye
region. Other recent studies indicate that the degree of neural
mance in ASD subjects (Pelphrey et al., 2005; Schultz et al.,
2005b; Dapretto et al., 2006). Thus, measuring parameters such
as eye tracking or autonomic function, a marker of emotional
ral activation. Last, the improving quality of imaging data now
allows statistical modeling of brain networks that seem to be
involved in social cognition and social perception, allowing one
ent brain areas work together to achieve functional behaviors. It
is now possible to model the temporal sequence of specific node
activation during prolonged behavioral tasks that may provide
insight into the manner by which brain regions contribute to
larger functional networks in normal subjects compared with
ASD (Just et al., 2004; Schultz et al., 2005b). In turn, these dis-
genetic alleles, thereby linking the pathway from gene to brain to
behavior. In this regard, neuroimaging studies could form the
glue that binds genetics to behavior.
The foregoing evidence indicates that ASD involves changes in
regional brain anatomy and functional neural networks and
likely results from abnormal regulation of multiple ontogenetic
processes. What underlies the abnormal brain development?
Studies of human populations indicate that ASD is primarily a
heritable disorder. We cannot exclude of course the possibility
that other factors also contribute to the manifestations of the
ASD concordance rates in monozygotic and dizygotic twins in-
sion suggest that it is polygenic, involving 3–15 alleles per indi-
vidual with complex gene–gene and/or gene–environment
effects (Risch et al., 1999; Szatmari, 1999). Genome-wide linkage
scans have been used to map the location of susceptibility genes.
tistical methods. Although few findings reach the Lander and
Kruglyak (1995) criteria for statistical significance, there is con-
vergence of suggestive linkages on chromosomes 2q, 7q, and 16p
(Wassink et al., 2004; Xu et al., 2004). Over 100 candidate genes
have been studied (Wassink et al., 2004), but few findings have
been replicated. Very recently, however, association of the cere-
bellar developmental patterning gene ENGRAILED 2 with ASD
has been reported (Gharani et al., 2004) and replicated in three
separate populations (Fig. 2) (Benayed et al., 2005). As the first
genetic allele to be reproducibly associated with ASD, it may
are other promising candidate genes, including the UBE3A locus
on chromosome 15q11–13, and the serotonin transporter gene
on chromosome 17q (Devlin et al., 2005). Analysis of ASD cases
form gyrus to faces in an adolescent male with ASD (right) compared with an age- and IQ-
cantly more active during perception of faces; signals in blue show areas more active during
variety of cognitive and perceptual tasks that are explicitly social in nature. Some evidence
(hypoactive during theory of mind tasks, i.e., when taking another person’s perspective); A,
6900 • J.Neurosci.,June28,2006 • 26(26):6897–6906DiCicco-Bloometal.•Mini-Review
pool samples and thus maximize statistical power. The examina-
tion of specific ASD-related phenotypes (endophenotypes, e.g.,
There has also been considerable attention to the possible
contribution of environmental factors (London, 2000). Several
prenatal exposures have been associated empirically with ASD
including thalidomide, certain viral infections, and maternal an-
et al., 2005). Although these factors independently account for
few cases, environmental factors may interact with genetic sus-
ceptibility to increase the likelihood of ASD. For example, some
data implicate a possible role of immune factors, including an
autoantibodies to neural antigens (Ashwood and Van de Water,
2004; Connolly et al., 2006).
Rationales for model development
diversity within each core symptom domain, it is not surprising
that there is no single animal model that captures all of the mo-
lecular, cellular, or organismic features of ASD. Challenged by
this complexity, one useful approach has been to focus on single
features to study the underlying mechanisms (DiCicco-Bloom,
2005). Based on the available neuroimaging, genetic, and patho-
logical evidence of a developmental origin, animal studies have
followed four general approaches or rationales, which may be
categorized as fundamental neurobiology, endophenotypic, ge-
netic, and pathogenetic.
The fundamental neurobiology approach posits that basic
mechanisms are conserved among organisms and are expanded
on or modified through evolution. By defining molecular and
cellular mechanisms that regulate brain region development or
mediate cognitive functions, we can identify molecular targets
whose disruption may contribute to an ASD-related abnormal-
ity. For example, research on oxytocin/vasopressin indicates that
these neuropeptides participate in social recognition, affiliation,
and maternal–infant bonding across many species. Conse-
quently, genetic findings in the animal model are now being ap-
et al., 2005). Language learning in the songbird is another inter-
esting model, in which auditory input, song imitation, and
FoxP1/2 gene expression demonstrate parallels to human lan-
guage (Teramitsu et al., 2004). Finally, growth factor regulation
of neurogenesis in ASD-affected regions including the cerebral
cortex, hippocampus, and cerebellum indicate that proliferation
growth factor), IGF1 (insulin-like growth factor), SHH (sonic
hedgehog) (Vaccarino et al., 1999; Wechsler-Reya and Scott,
antimitogenic [PACAP (pituitary adenylate cyclase-activating
polypeptide) (Suh et al., 2001; Carey et al., 2002; Nicot et al.,
2002)] signals. Acting via cognate receptors, growth factors elicit
rapid changes in select cell cycle regulators that determine
and antimitogenic signals from ligand to receptor to cell cycle
regulator, all potential candidate genes.
The endophenotype approach investigates mechanisms un-
derlying defined traits that are not necessarily confined to a spe-
cific diagnostic category such as ASD, specific language impair-
ment, or attention disorders. ASD-related endophenotypes
include social isolation, changes in neurotransmitter systems, or
deficits of Purkinje neurons. Using newborn and adult nonhu-
man primates, such studies have examined roles of the hip-
used modifications of newborn rearing conditions (Winslow,
Engrailed 2 (En2) has been of particular interest for several rea-
sons. Specifically, En2 deletion or overexpression produces Pur-
kinje cell deficits; the diminished posterior cerebellar vermis and
identified by several ASD genome linkage scans. Studies of En2
gene overexpression (Baader et al., 1998; Benayed et al., 2005) as
well as gene deletion have been performed in vivo and in vitro
and reduces neuronal differentiation, mechanisms that could
conceivably contribute to ASD cerebellar neuropathology.
The genetic approach uses targeted mutations in mice to de-
fine mechanisms regulated by genes considered important for
ASD. The genes tested are known to cause ASD, are associated
with ASD, or have been proposed as candidate genes based on
their developmental functions or localization to chromosomal
regions identified by linkage analyses. A well characterized ASD-
results from mutations in either of two genes, hamartin and tu-
berin, that function as tumor suppressors and interact with pro-
tein translational machinery. Other Mendelian genetic disorders
manifesting aspects of ASD include fragile X mental retardation,
Rett’s, Prader-Willi, Angelman, and Smith-Lemli-Opitz syn-
dromes (Polleux and Lauder, 2004; Xu et al., 2004). The related
mouse mutants are under active investigation. One may specu-
late that less severe alleles at these loci could contribute to ASD
susceptibility in the absence of the primary clinical condition.
Regarding disease-associated genes, EN2 exhibits replication of a
specific genetic allele with ASD (Benayed et al., 2005). However,
for several genes, there is repeated association but not for the
same single nucleotide polymorphism (SNP). Should these dif-
ferent SNPs produce similarly altered gene function, one may
consider the possibility that different disease alleles may equally
disrupt gene function to contribute to disease susceptibility
in neurotransmitter systems (serotonin transporter). However,
final conclusions about the contributions to ASD susceptibility
must await genetic replication in separate affected populations
a C/T polymorphism. Significant association for the A allele of rs1861972 and the C allele of
2004; Benayed et al., 2005) [ASD (Mendelian Inheritance in Man MIM 608636); EN2 (MIM
DiCicco-Bloometal.•Mini-ReviewJ.Neurosci.,June28,2006 • 26(26):6897–6906 • 6901
ASD in a restricted manner: in two families, mutations in synap-
tic adhesion molecules (neuroligin 3 and 4) account for ASD.
Consequently, expression of mutant neuroligins in cells and an-
imals is being used to examine the roles of synaptodendritic de-
fects in cognitive disorders like ASD.
The pathogenetic approach examines the effects of known or
infections, and hindbrain congenital syndromes. The observa-
tion that 4 of 15 human embryos exposed on gestational days
20–24 to the teratogenic antinausea drug thalidomide displayed
ASD led to the proposal that insults to the hindbrain, at the time
that the neural tube is closing and craniocerebellar neurons are
being generated, may contribute to ASD (Stro ¨mland et al., 1994;
Arndt et al., 2005). Signs of ASD are observed in several congen-
ital hindbrain syndromes including CHARGE, Goldenhar, and
Mobius (Miller et al., 2005). Rodier et al. (1996) mimicked this
to valproic acid, a common anticonvulsant associated with ASD
and cognitive deficits. These animals developed cranial and Pur-
kinje neuron deficits and behavioral abnormalities in eye-blink
conditioning as observed in ASD (Arndt et al., 2005). ASD has
also been associated with gestational rubella and possibly influ-
enza. Adult offspring of pregnant mice that sustain human
influenza-induced pneumonia exhibit abnormalities in behavior
as well as in molecular markers for neurons, glia, and inflamma-
suggests that circulating maternal cytokines could be primary
mediators of pathogenesis (Shi et al., 2005), an intriguing result
given MHC (major histocompatibility complex) class I expres-
sion and function in axonal pathfinding and synaptogenesis
(Boulanger and Shatz, 2004).
Mouse behavioral models of ASD
An ideal mouse model of ASD should display behavioral symp-
toms with face validity for the defining symptoms of (1) recipro-
cal social interactions, (2) social communication, and (3) stereo-
typed, ritualistic, and repetitive behaviors and/or narrow
restricted interests. Tasks that could examine these behavioral
species-relevant tasks, and certain limitations may be expected.
Tasks of social approach measure the propensity of mice to
spend time with another animal rather than nonsocial novel ob-
jects. These tasks measure detailed components of the social in-
social approach is initiated by the subject mouse has been fully
characterized (Fig. 3) (Moy et al., 2004; Nadler et al., 2004). In
dard video-tracking and observer event-recording methods have
been used widely to quantify social interaction, social recogni-
tion, and social memory (Insel and Young, 2001; Winslow and
effectively in mice using olfactory and auditory communication
tasks (Winslow and Insel, 2002; Wrenn et al., 2003; Blanchard et
al., 2003; Petrulis et al., 2005). Finally, stereotypies, persevera-
tion, and restricted interests can be investigated in mice using
exploratory choices and reversal tasks (Crawley, 2004; Presti et
Thorough phenotypic assessment of general health, sensory
abilities, and motor functions will be essential to rule out potential
artifacts caused by physical disabilities (Crawley, 2000). For exam-
would be a useful means to evaluate potential treatments for core
Social behavior and the role of neuropeptides
Animal models of normal social behavior may provide insights
regarding the social phenotypes in individuals with ASD. Two
sets of studies in rodents nicely illustrate this point. The first
capitalizes on the strikingly different social behavior of prairie
social, craves social contact, and forms enduring social bonds
with its mate (Carter et al., 1995; Young and Wang, 2004). In
contrast, the promiscuous montane vole is socially aloof, prefers
to spend time alone, and does not form social bonds. The neu-
ing this behavior (Young and Wang, 2004). Comparative neuro-
anatomical studies suggest that the behavior is a result of
differences in the brain expression patterns of these peptide re-
ceptors. Specifically, oxytocin and vasopressin receptors are
highly expressed in the mesolimbic reward structures, nucleus
prairie vole reveals that a polymorphic repetitive element likely
determines its expression pattern (Young et al., 1999) such that
individual differences in the length of the unstable element are
responsible for individual differences in social behavior (Ham-
mock and Young, 2005). These animal studies triggered the ex-
amination of the human vasopressin receptor gene (avpr1a) that
of this polymorphism are associated with ASD (Kim et al., 2001;
contributor to ASD, variants may interact with other genetic or
environmental factors to contribute to the social behavioral
Knock-out mice for oxytocin and vasopressin receptors have
confirmed the critical role of these genes in regulating social be-
these knock-outs display social amnesia, indicating a deficit in
social stimuli processing. Oxytocin knock-out mice pups do not
display normal levels of ultrasonic distress vocalizations when
with a stopwatch. Containing the stranger mouse in the wire cup ensures that all social ap-
6902 • J.Neurosci.,June28,2006 • 26(26):6897–6906 DiCicco-Bloometal.•Mini-Review
separated from their mother (Winslow et al., 2000), and they
display increased latencies to approach their mother. These be-
tocin (Modahl et al., 1998). Insights gained from these animal
human avpr1a gene, and may lead to development of targeted
treatment strategies such as the use of oxytocin as a therapy for
levels of analysis are beginning to define basic neurobiological
mechanisms that could underlie ASD. In turn, this may lead to
improvements in disease diagnosis, early and effective treat-
ments, and ultimately, prevention.
What developments in diagnosis, pathogenesis, and treatment
may we look forward to in the near future? Given the develop-
mental origins of ASD and the identification of early behavioral
to diagnose ASD during the first year of life. Early diagnosis may
allow more effective teaching and behavioral strategies to maxi-
mize developmental progress to enrich the affected child’s expe-
rience and possibly lessen further mal-development. The struc-
tural, metabolic, and functional neuroimaging is characterizing
the disordered ASD brain at several levels. Overall, the postnatal
brain growth trajectory is increased, with the greatest differences
occurring in rostral cerebral cortex, amygdala, and cerebellar
hemispheres and reflecting greater changes in white than gray
matter. However, the underlying etiology remains to be defined.
It is unknown whether or not increased brain size reflects a nor-
mal balance of cell types, although functional connectivity and
activity relationships among specific brain regions are disturbed.
addressed soon as ongoing stereological studies of forebrain and
hindbrain regions reach completion. The increasing precision of
fMRI may reveal correlations of network activity with individual
symptoms in individual patients, providing a means to assess
We are also on the verge of genetic discoveries that will focus
attention on a number of developmental regulators and pro-
cesses, neurotransmitter and synaptic components and, poten-
tially, novel genetic mechanisms that contribute to ASD suscep-
tibility in the context of specific environmental factors. Progress
in animal models should allow investigators to examine specific
ASD components using approaches based on the fundamental
neurobiology, endophenotypes, susceptibility genes, and patho-
genetic factors. Hopefully, such animal models will allow addi-
tional definition of the molecular pathways in human ASD pop-
have led to new human genetic studies, and the association of
EN2 with ASD raises questions about the relationships of geno-
type to brain morphology, on the one hand, and the range of
clinical symptoms, on the other. From a broader perspective,
successful communication among investigators across tradi-
tional disciplinary boundaries is essential to establish the validity
the clinician faces the challenge of fitting newly defined develop-
mental and molecular mechanisms with clinical subpopulations
for additional study. We are in an exciting time for ASD research
with the convergence of enhanced societal concern, increased
research support, and the emerging realization by neurobiolo-
gists that studies of ASD may lead to fundamental insights into
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