A synaptic trek to autism.
ABSTRACT Autism spectrum disorders (ASD) are diagnosed on the basis of three behavioral features namely deficits in social communication, absence or delay in language, and stereotypy. The susceptibility genes to ASD remain largely unknown, but two major pathways are emerging. Mutations in TSC1/TSC2, NF1, or PTEN activate the mTOR/PI3K pathway and lead to syndromic ASD with tuberous sclerosis, neurofibromatosis, or macrocephaly. Mutations in NLGN3/4, SHANK3, or NRXN1 alter synaptic function and lead to mental retardation, typical autism, or Asperger syndrome. The mTOR/PI3K pathway is associated with abnormal cellular/synaptic growth rate, whereas the NRXN-NLGN-SHANK pathway is associated with synaptogenesis and imbalance between excitatory and inhibitory currents. Taken together, these data strongly suggest that abnormal synaptic homeostasis represent a risk factor to ASD.
- SourceAvailable from: George Fuchs[Show abstract] [Hide abstract]
ABSTRACT: Background: Oxidative stress and abnormal DNA methylation have been implicated in the pathophysiology of autism. The metabolic pathology of autism is relatively unexplored although metabolic imbalance is implicated in the pathogenesis of multiple other neurobehavioral disorders. An abnormal accumulation or deficit of specific metabolites in a defined pathway can provide clues into relevant candidate genes and/or environmental exposures. In addition, the identification of precursor-product metabolite imbalance can inform targeted intervention strategies to restore metabolic balance and potentially improve symptoms of autism. We have investigated metabolic pathways essential for cellular methylation and antioxidant capacity and the functional impact of metabolic imbalance on genome-wide DNA hypomethylation and protein/DNA oxidative damage in children with autism. These metabolic pathways regulate the distribution of precursors for DNA synthesis (proliferation), DNA methylation (epigenetic regulation of gene expression) and glutathione synthesis (redox/antioxidant defense capacity). Previously, we reported that the metabolic profile of many children with autism is consistent with reduced methylation capacity and a more oxidized microenvironment. Objectives: To determine whether methylation and antioxidant metabolic profile differs between case children, unaffected siblings, and age-matched control children and to determine whether the metabolic imbalance is accompanied by DNA hypomethylation and protein/DNA oxidative damage. Methods: Subjects included 162 children, ages 3-10, who were participants in the autism IMAGE study (Integrated Metabolic And Genomic Endeavor) at Arkansas Children’s Hospital Research Institute. The IMAGE cohort is comprised of 162 children including of 68 case children, 54 age-matched controls and 40 unaffected siblings. Children with autistic disorder were diagnosed using DSM-IV (299.0), ADOS and/or CARS >30. Fasting plasma samples were analyzed for folate-dependent transmethylation and transsulfuration metabolites and 3-nitrotyrosine (oxidized protein derivative) using HPLC with electrochemical detection. Genome-wide DNA methylation (as %5-methylcytosine) and the oxidized DNA adduct 8-oxo-deoxyguanine were quantified with Dionex HPLC-UV system coupled to an electrospray ionization (ESI) tandem mass spectrometer. Results: In a pair-wise comparison, the overall metabolic profile of the unaffected siblings differed significantly from their autistic siblings but was not different from unrelated control children. In addition, we report new evidence of genome-wide DNA hypomethylation (epigenetic dysregulation) and oxidative protein/DNA damage in children with autism that was not present in their paired siblings or in unaffected control children. Conclusions: These data indicate that the deficit in antioxidant and methylation capacity is autism-specific and is associated with DNA hypomethylation (epigenetic dysregulation) and oxidative damage. Further, these results suggest a plausible mechanism by which environmental stressors might modulate the genetic predisposition to autism. Acknowledgement: This research was supported with funding from the National Institute of Child Health and Development (RO1 HD051873; SJJ) and Department of Defense (AS073218P1; SJJ)International Meeting for Autism Research 2011; 05/2011
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ABSTRACT: Autism has been described as a disorder of general neural processing, but the particular processing characteristics that might be abnormal in autism have mostly remained obscure. Here, we present evidence of one such characteristic: poor evoked response reliability. We compared cortical response amplitude and reliability (consistency across trials) in visual, auditory, and somatosensory cortices of high-functioning individuals with autism and con-trols. Mean response amplitudes were statistically indistinguishable across groups, yet trial-by-trial response reliability was significantly weaker in autism, yielding smaller signal-to-noise ratios in all sensory systems. Response reliability differences were evident only in evoked cortical responses and not in ongoing resting-state activity. These findings reveal that abnormally unreliable cortical responses, even to elementary nonsocial sensory stimuli, may represent a fundamental physiological alteration of neural processing in autism. The results motivate a critical expansion of autism research to determine whether (and how) basic neural processing proper-ties such as reliability, plasticity, and adaptation/ habituation are altered in autism.
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ABSTRACT: Spines are small cytoplasmic extensions of dendrites that form the postsynaptic compartment of the majority of excitatory synapses in the mammalian brain. Alterations in the numerical density, size, and shape of dendritic spines have been correlated with neuronal dysfunction in several neurological and neurodevelopmental disorders associated with intellectual disability, including Rett syndrome (RTT). RTT is a progressive neurodevelopmental disorder associated with intellectual disability that is caused by loss of function mutations in the transcriptional regulator methyl CpG-binding protein 2 (MECP2). Here, we review the evidence demonstrating that principal neurons in RTT individuals and Mecp2-based experimental models exhibit alterations in the number and morphology of dendritic spines. We also discuss the exciting possibility that signaling pathways downstream of brain-derived neurotrophic factor (BDNF), which is transcriptionally regulated by MeCP2, offer promising therapeutic options for modulating dendritic spine development and plasticity in RTT and other MECP2-associated neurodevelopmental disorders.Frontiers in Neuroanatomy 09/2014; 8:97. · 4.06 Impact Factor
Available online at www.sciencedirect.com
A synaptic trek to autism
Autism spectrum disorders (ASD) are diagnosed on the basis
of three behavioral features namely deficits in social
communication, absence or delay in language, and
stereotypy. The susceptibility genes to ASD remain largely
unknown, but two major pathways are emerging. Mutations in
TSC1/TSC2, NF1, or PTEN activate the mTOR/PI3K pathway
and lead to syndromic ASD with tuberous sclerosis,
neurofibromatosis, or macrocephaly. Mutations in NLGN3/4,
SHANK3, or NRXN1 alter synaptic function and lead to mental
PI3K pathway is associated with abnormal cellular/synaptic
growth rate, whereas the NRXN–NLGN–SHANK pathway is
associated with synaptogenesis and imbalance between
excitatory and inhibitory currents. Taken together, these data
strongly suggest that abnormal synaptic homeostasis
represent a risk factor to ASD.
1Human Genetics and Cognitive Functions, Institut Pasteur, 25 rue du
Docteur Roux, 75015 Paris, France
2University Denis Diderot, Paris 7, Paris, France
Corresponding author: Bourgeron, Thomas (email@example.com)
Current Opinion in Neurobiology 2009, 19:231–234
This review comes from a themed issue on
Edited by Takao Hensch and Andrea Brand
Available online 21st June 2009
0959-4388/$ – see front matter
# 2009 Elsevier Ltd. All rights reserved.
Autismaffects about 0.7% ofchildren and ischaracterized
by deficits in social communication, absence or delay in
language, and stereotyped and repetitive behaviors.
Beyond this unifying definition, lies a spectrum of dis-
orders/conditions, ranging from severe impairments to
mild personality traits. Autism spectrum disorders
(ASD) are diagnosed before three years of age, a period
characterized by intense synaptogenesis in the human
brain . This review reports recent genetic and neuro-
biological findings that highlight two routes leading to
ASD: abnormal cellular/synaptic growth and imbalance
between inhibitory and excitatory synaptic currents.
Abnormal cellular/synaptic growth in ASD
The hypothesis that abnormal cellular/synaptic growth
may increase the risk of having ASD, was first suggested
by the recurrent observation of macrocephaly in 10–30%
of the patients with ASD [2–4]. The head circumference
may be normal at birth, but during the first four years of
life, an overgrowth of the brain is observed [5,6]. The
nature of the macrocephaly — too many neurons, glial
cells,synapses,orlargercells — remainsdifficulttoestab-
lish. However, studies on neurofibromatosis, tuberous
sclerosis, and Cowden/Lhermitte–Duclos syndromes
have provided interesting information on the link be-
tween abnormal growth rate and ASD . These genetic
syndromes associate both susceptibility to ASD and
macrocephaly and are caused by mutations in the tumor
suppressor genes NF1, TSC1/TSC2, and PTEN . In
tuberous sclerosis, mutations of TSC1/TSC2 induce cor-
tical developmental malformations called tubers. These
tubers were originally thought to be the cause of ASD
when their locations in the brain were overlapping areas
important for social communication and language. How-
ever, studies in mice showing that loss of Tsc1/Tsc2 or Pten
results in neuronal hypertrophy have led to the hypoth-
esis that susceptibility to ASD was not because of the
tubers, but to an abnormal shape and size of the neurons
Interestingly, NF1, TSC1/TSC2, and PTEN act in a
common pathway as negative effectors of the rapamy-
cin-sensitive mTOR–raptor complex (mTORC1), a
major regulator of cellular growth in mitotic cells .
Mutations are predicted to enhance the mTORC1 com-
plex, a signal activated by a sequential kinase cascade
downstream of phosphoinositide-3 kinase (PI3K) path-
way. This pathway may also be modulated by serotonin
since macrocephaly and abnormal behaviors are exacer-
bated in mice with both Pten and serotonin transporter
mutations . A stimulating hypothesis proposed by
Kelleher and Bear, suggests that the increase of the
mTOR pathway could lead to abnormal synaptic function
owing to an excess of protein synthesis at the synapse
Abnormal balance between inhibitory and
excitatory currents in ASD
The possibility that alteration of synaptic functions could
lead to ASD was first indicated by the phenotypic overlap
between autism, fragile X syndrome, and Rett syndrome
[12,13]. In addition, the key role of the excitatory/inhibi-
tory currents in ASD was further supported by the obser-
vation that 10–30% of patients with ASD have epilepsy
. The synaptic hypothesis was confirmed by the
identification of mutations affecting the postsynaptic cell
adhesion molecules Neuroligins (NLGN) in individuals
with ASD [15??,16]. At the functional level,the mutations
Current Opinion in Neurobiology 2009, 19:231–234
were found to alter the property of the NLGN to trigger
synapse formation in cultured neuronal cells . NLGN
mutations probably concern a limited number of cases
(<1% of the individuals), but following these initial
results, mutations in other synaptic proteins such as
SHANK3, NRXN1, CNTNAP2, CNTN3/4, and PCDH9/
10 were identified in patients with ASD [18–25]. Inter-
estingly, NRXN1 codes for the presynaptic binding part-
ner of NLGNs, CNTNAP2 (Caspr2) possess strong
of the postsynaptic density that binds to NLGN and
regulates the size and shape of dendritic spines .
Only limited data are available for understanding the role
of these proteins in the human brain, but studies using
neuronal cell culture and animal models have provided
crucial information. Firstly, NLGNs
enhance synapse formation in vitro [27??], but are not
required for the generation of synapses in vivo [28??].
Therefore, NLGNs may not establish synapses, but may
contribute to the activity-dependent formation of neural
circuits [29?]. Secondly, NLGNs and NRXNs are emer-
ging as central organizing molecules for excitatory gluta-
matergic and inhibitory GABAergic synapses in the
mammalian brain [30,31]. The mutant mice carrying a
R451C Nlgn3 mutation identified in two brothers with
ASD displays an increased number of GABAergic
synapses and inhibitory currents . An imbalance of
inhibition and excitation was also observed in MeCP2
knockout  and in several mice proposed as model of
autism such as the Caps2 knockout  or mice subject to
prenatal valproate treatment . Interestingly, the link
between GABA function and spine pruning has been
identified during a critical period of brain development
when individual experience is essential for the normal
development of the neuronal network . Therefore,
impaired inhibitory–excitatory balance can be manifest as
a shifted critical period for brain development  or an
alteration of sensory processing, such as reduced gamma
oscillations in FMRP knockout mice  as seen also in
ASD . Taken together, these results strongly suggest
that synapse homeostasis and specificity play an import-
ant role in the susceptibility to ASD.
Atypical neuronal networks in ASD
In the human cerebral cortex, the first synapses are
evident at the 40th day after conception. Thereafter,
the rate of synapse formation and pruning exhibit distinct
phases, the most dramatic change takes place during the
perinatal period (Figure 1). During the first three years of
life, synaptic contacts are formed, but only some will be
stabilized. This selection process represents a key step in
the cognitive development of the child. The NLGN–
NRXN–SHANK pathway is probably required during
this stabilization phase of the synapse in response to
neuronal activity. Strikingly, the role of the NLGN–
NRXN–SHANK pathway in the development of social
interaction seems to be conserved in other species.
Schematic representation of the different phases of synaptogenesis in the human brain. During the first three years of life, an excess of cell/synaptic
growth rate and inhibitory currents could increase the risk of ASD. Mutations within the mTOR/PI3K pathway lead to an excess of synaptic/cell growth.
Mutations within the NRXN–NLGN–SHANK pathway lead to abnormal synaptogenesis and excess of inhibitory currents. The arrows entering the red
zone illustrate the excess of synaptic/cell growth and inhibitory currents during early brain development.
Current Opinion in Neurobiology 2009, 19:231–234www.sciencedirect.com
Indeed, knockout mice for Nlgn4 display reduced social
interactions and ultrasonic vocalizations (USV) at the
adult stage [40??]. Mice carrying the R451C mutation
in Nlgn3 display normal  to reduced social interaction
 at the adult stage and a reduction of isolation calls in
pups . However, knockout Nlgn4 and mutant knockin
Nlgn3 display normal to enhanced learning when com-
pared with wild-type mice [32,40??]. The same is true for
the mice carrying a null mutation of Shank1, which
exhibits increased anxiety-related behavior, but show
enhanced spatial learning .
One of the main challenges for basic scientists and
clinicians is to understand how far abnormal cell/synaptic
growth and synaptic function could be reversed. Remark-
ably, in mice with Tsc1/Tsc2 or Pten mutations, the use of
rapamycin, a specific inhibitor of mTORC1, can prevent
and reverse neuronal hypertrophy, resulting in the ame-
lioration of the behavior [43?,44?]. Similarly, abnormal
synaptic functions could be reversed in adult mice model
for fragile X or Rett syndrome [45?,46,47]. The possibility
to reverse the social and USV alterations of the Nlgn3/4
mutant mice has not been tested yet, but the recent
results obtained on mice model for fragile X or Rett
syndrome provide new hopes for the treatment of ASD.
New routes to ASD?
ASD, but most probably many other tracks can lead to this
complex syndrome. Furthermore, even when a pathway is
identified, the diversity of genotype–phenotype relation-
ships observed in patients with ASD indicates that other
modulators such as serotonin and/or melatonin may play
recent results have shed light on the origin of ASD and we
are confident that new pathways will be identified soon to
better understand the many facets of ASD.
This work was supported by the Pasteur Institute, University Denis Diderot
Paris 7, INSERM, CNRS, Assistance Publique-Ho ˆpitaux de Paris, FP6
ENI-NET, FP6 EUSynapse, Fondation Orange, Fondation de France, and
Fondation pour la Recherche Me ´dicale, Fondation FondaMentale.
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Current Opinion in Neurobiology 2009, 19:231–234www.sciencedirect.com