A Model of Functional Brain Connectivity and Background Noise as a Biomarker for Cognitive Phenotypes: Application to Autism

We present an efficient approach to discriminate between typical and atypical brains from macroscopic neural dynamics recorded as magnetoencephalograms (MEG). Our approach is based on the fact that spontaneous brain activity can be accurately described with stochastic dynamics, as a multivariate Ornstein-Uhlenbeck process (mOUP). By fitting the data to a mOUP we obtain: 1) the functional connectivity matrix, corresponding to the drift operator, and 2) the traces of background stochastic activity (noise) driving the brain. We applied this method to investigate functional connectivity and background noise in juvenile patients (n = 9) with Asperger’s syndrome, a form of autism spectrum disorder (ASD), and compared them to age-matched juvenile control subjects (n = 10). Our analysis reveals significant alterations in both functional brain connectivity and background noise in ASD patients. The dominant connectivity change in ASD relative to control shows enhanced functional excitation from occipital to frontal areas along a parasagittal axis. Background noise in ASD patients is spatially correlated over wide areas, as opposed to control, where areas driven by correlated noise form smaller patches. An analysis of the spatial complexity reveals that it is significantly lower in ASD subjects. Although the detailed physiological mechanisms underlying these alterations cannot be determined from macroscopic brain recordings, we speculate that enhanced occipital-frontal excitation may result from changes in white matter density in ASD, as suggested in previous studies. We also venture that long-range spatial correlations in the background noise may result from less specificity (or more promiscuity) of thalamo-cortical projections. All the calculations involved in our analysis are highly efficient and outperform other algorithms to discriminate typical and atypical brains with a comparable level of accuracy. Altogether our results demonstrate a promising potential of our approach as an efficient biomarker for altered brain dynamics associated with a cognitive phenotype.     

Stronger Neural Modulation by Visual Motion Intensity in Autism Spectrum Disorders

Theories of autism spectrum disorders (ASD) have focused on altered perceptual integration of sensory features as a possible core deficit. Yet, there is little understanding of the neuronal processing of elementary sensory features in ASD. For typically developed individuals, we previously established a direct link between frequency-specific neural activity and the intensity of a specific sensory feature: Gamma-band activity in the visual cortex increased approximately linearly with the strength of visual motion. Using magnetoencephalography (MEG), we investigated whether in individuals with ASD neural activity reflect the coherence, and thus intensity, of visual motion in a similar fashion. Thirteen adult participants with ASD and 14 control participants performed a motion direction discrimination task with increasing levels of motion coherence. A polynomial regression analysis revealed that gamma-band power increased significantly stronger with motion coherence in ASD compared to controls, suggesting excessive visual activation with increasing stimulus intensity originating from motion-responsive visual areas V3, V6 and hMT/V5. Enhanced neural responses with increasing stimulus intensity suggest an enhanced response gain in ASD. Response gain is controlled by excitatory-inhibitory interactions, which also drive high-frequency oscillations in the gamma-band. Thus, our data suggest that a disturbed excitatory-inhibitory balance underlies enhanced neural responses to coherent motion in ASD.     

Luminance- and Texture-Defined Information Processing in School-Aged Children with Autism

According to the complexity-specific hypothesis, the efficacy with which individuals with autism spectrum disorder (ASD) process visual information varies according to the extensiveness of the neural network required to process stimuli. Specifically, adults with ASD are less sensitive to texture-defined (or second-order) information, which necessitates the implication of several cortical visual areas. Conversely, the sensitivity to simple, luminance-defined (or first-order) information, which mainly relies on primary visual cortex (V1) activity, has been found to be either superior (static material) or intact (dynamic material) in ASD. It is currently unknown if these autistic perceptual alterations are present in childhood. In the present study, behavioural (threshold) and electrophysiological measures were obtained for static luminance- and texture-defined gratings presented to school-aged children with ASD and compared to those of typically developing children. Our behavioural and electrophysiological (P140) results indicate that luminance processing is likely unremarkable in autistic children. With respect to texture processing, there was no significant threshold difference between groups. However, unlike typical children, autistic children did not show reliable enhancements of brain activity (N230 and P340) in response to texture-defined gratings relative to luminance-defined gratings. This suggests reduced efficiency of neuro-integrative mechanisms operating at a perceptual level in autism. These results are in line with the idea that visual atypicalities mediated by intermediate-scale neural networks emerge before or during the school-age period in autism.     

Theta rhythms coordinate hippocampal-prefrontal interactions in a spatial memory task

Decision-making requires the coordinated activity of diverse brain structures. For example, in maze-based tasks, the prefrontal cortex must integrate spatial information encoded in the hippocampus with mnemonic information concerning route and task rules in order to direct behavior appropriately. Using simultaneous tetrode recordings from CA1 of the rat hippocampus and medial prefrontal cortex, we show that correlated firing in the two structures is selectively enhanced during behavior that recruits spatial working memory, allowing the integration of hippocampal spatial information into a broader, decision-making network. The increased correlations are paralleled by enhanced coupling of the two structures in the 4- to 12-Hz theta-frequency range. Thus the coordination of theta rhythms may constitute a general mechanism through which the relative timing of disparate neural activities can be controlled, allowing specialized brain structures to both encode information independently and to interact selectively according to current behavioral demands.     

Theta Rhythms Coordinate Hippocampal–Prefrontal Interactions in a Spatial Memory Task

Decision-making requires the coordinated activity of diverse brain structures. For example, in maze-based tasks, the prefrontal cortex must integrate spatial information encoded in the hippocampus with mnemonic information concerning route and task rules in order to direct behavior appropriately. Using simultaneous tetrode recordings from CA1 of the rat hippocampus and medial prefrontal cortex, we show that correlated firing in the two structures is selectively enhanced during behavior that recruits spatial working memory, allowing the integration of hippocampal spatial information into a broader, decision-making network. The increased correlations are paralleled by enhanced coupling of the two structures in the 4- to 12-Hz theta-frequency range. Thus the coordination of theta rhythms may constitute a general mechanism through which the relative timing of disparate neural activities can be controlled, allowing specialized brain structures to both encode information independently and to interact selectively according to current behavioral demands.     

Defining language impairments in a subgroup of children with autism spectrum disorder

Autism spectrum disorder(ASD) is diagnosed on the basis of core impairments in pragmatic language skills, which are found across all ages and subtypes. In contrast, there is significant heterogeneity in language phenotypes, ranging from nonverbal to superior linguistic abilities, as defined on standardized tests of vocabulary and grammatical knowledge. The majority of children are verbal but impaired in language, relative to age-matched peers. One hypothesis is that this subgroup has ASD and co-morbid specific language impairment(SLI). An experiment was conducted comparing children with ASD to children with SLI and typically developing controls on aspects of language processing that have been shown to be impaired in children with SLI: repetition of nonsense words. Patterns of performance among the children with ASD and language impairment were similar to those with SLI, and contrasted with the children with ASD and no language impairment and typical controls, providing further evidence for the hypothesis that a subgroup of children with ASD has co-morbid SLI. The findings are discussed in the context of brain imaging studies that have explored the neural bases of language impairment in ASD and SLI, and overlap in the genes associated with elevated risk for these disorders.     

Auditory Processing in High-Functioning Adolescents with Autism Spectrum Disorder

Autism Spectrum Disorder (ASD) is a pervasive developmental disorder including abnormalities in perceptual processing. We measure perception in a battery of tests across speech (filtering, phoneme categorization, multisensory integration) and music (pitch memory, meter categorization, harmonic priming). We found that compared to controls, the ASD group showed poorer filtering, less audio-visual integration, less specialization for native phonemic and metrical categories, and a higher instance of absolute pitch. No group differences were found in harmonic priming. Our results are discussed in a developmental framework where culture-specific knowledge acquired early compared to late in development is most impaired, perhaps because of early-accelerated brain growth in ASD. These results suggest that early auditory remediation is needed for good communication and social functioning.     

Gamma activation in young people with autism spectrum disorders and typically-developing controls when viewing emotions on faces

Background

Behavioural studies have highlighted irregularities in recognition of facial affect in children and young people with autism spectrum disorders (ASDs). Recent findings from studies utilising electroencephalography (EEG) and magnetoencephalography (MEG) have identified abnormal activation and irregular maintenance of gamma (>30 Hz) range oscillations when ASD individuals attempt basic visual and auditory tasks.

Methodology/Principal Fndings

The pilot study reported here is the first study to use spatial filtering techniques in MEG to explore face processing in children with ASD. We set out to examine theoretical suggestions that gamma activation underlying face processing may be different in a group of children and young people with ASD (n = 13) compared to typically developing (TD) age, gender and IQ matched controls. Beamforming and virtual electrode techniques were used to assess spatially localised induced and evoked activity. While lower-band (3–30 Hz) responses to faces were similar between groups, the ASD gamma response in occipital areas was observed to be largely absent when viewing emotions on faces. Virtual electrode analysis indicated the presence of intact evoked responses but abnormal induced activity in ASD participants.

Conclusions/Significance

These findings lend weight to previous suggestions that specific components of the early visual response to emotional faces is abnormal in ASD. Elucidation of the nature and specificity of these findings is worthy of further research.     

Eye Tracking Young Children with Autism

The rise of accessible commercial eye-tracking systems has fueled a rapid increase in their use in psychological and psychiatric research. By providing a direct, detailed and objective measure of gaze behavior, eye-tracking has become a valuable tool for examining abnormal perceptual strategies in clinical populations and has been used to identify disorder-specific characteristics¹, promote early identification², and inform treatment³. In particular, investigators of autism spectrum disorders (ASD) have benefited from integrating eye-tracking into their research paradigms^4-7. Eye-tracking has largely been used in these studies to reveal mechanisms underlying impaired task performance⁸ and abnormal brain functioning⁹, particularly during the processing of social information^1,10-11. While older children and adults with ASD comprise the preponderance of research in this area, eye-tracking may be especially useful for studying young children with the disorder as it offers a non-invasive tool for assessing and quantifying early-emerging developmental abnormalities^2,12-13. Implementing eye-tracking with young children with ASD, however, is associated with a number of unique challenges, including issues with compliant behavior resulting from specific task demands and disorder-related psychosocial considerations. In this protocol, we detail methodological considerations for optimizing research design, data acquisition and psychometric analysis while eye-tracking young children with ASD. The provided recommendations are also designed to be more broadly applicable for eye-tracking children with other developmental disabilities. By offering guidelines for best practices in these areas based upon lessons derived from our own work, we hope to help other investigators make sound research design and analysis choices while avoiding common pitfalls that can compromise data acquisition while eye-tracking young children with ASD or other developmental difficulties.     

Electrophysiological and Behavioral Outcomes of Berard Auditory Integration Training (AIT) in Children with Autism Spectrum Disorder

Autism is a pervasive developmental disorder of childhood characterized by deficits in social interaction, language, and stereotyped behaviors along with a restricted range of interests. It is further marked by an inability to perceive and respond to social and emotional signals in a typical manner. This might due to the functional disconnectivity of networks important for specific aspects of social cognition and behavioral control resulting in deficits of sensory information integration. According to several recent theories sensory processing and integration abnormalities may play an important role in impairments of perception, cognition, and behavior in individuals with autism. Among these sensory abnormalities, auditory perception distortion may contribute to many typical symptoms of autism. The present study used Berard’s technique of auditory integration training (AIT) to improve sound integration in children with autism. It also aimed to understand the abnormal neural and functional mechanisms underlying sound processing distortion in autism by incorporating behavioral, psychophysiological and neurophysiological outcomes. It was proposed that exposure to twenty 30-min AIT sessions (total 10 h of training) would result in improved behavioral evaluation scores, improve profile of cardiorespiratory activity, and positively affect both early [N1, mismatch negativity (MMN)] and late (P3) components of evoked potentials in auditory oddball task. Eighteen children with autism spectrum disorder (ASD) participated in the study. A group of 16 typically developing children served as a contrast group in the auditory oddball task. Autonomic outcomes of the study reflected a linear increase of heart rate variability measures and respiration rate. Comparison of evoked potential characteristics of children with ASD versus typically developing children revealed several group difference findings, more specifically, a delayed latency of N1 to rare and frequent stimuli, larger MMN; higher P3a to frequent stimuli, and at the same time delayed latency of P3b to rare stimuli in the autism group. Post-AIT changes in evoked potentials could be summarized as a decreased magnitude of N1 to rare stimuli, marginally lower negativity of MMN, and decrease of the P3a to frequent stimuli along with delayed latency and higher amplitude of the P3b to the rare stimuli. These evoked potential changes following completion of Berard AIT course are in a positive direction, making them less distinct from those recorded in age-matched group of typical children, thus could be considered as changes towards normalization. Parental questionnaires clearly demonstrated improvements in behavioral symptoms such as irritability, hyperactivity, repetitive behaviors and other important behavioral domains. The results of the study propose that more controlled research is necessary to document behavioral and psychophysiological changes resulting from Berard AIT and to provide explanation of the neural mechanisms of how auditory integration training may affect behavior and psychophysiological responses of children with ASD.     

Metabolomics as a Tool for Discovery of Biomarkers of Autism Spectrum Disorder in the Blood Plasma of Children

Background

The diagnosis of autism spectrum disorder (ASD) at the earliest age possible is important for initiating optimally effective intervention. In the United States the average age of diagnosis is 4 years. Identifying metabolic biomarker signatures of ASD from blood samples offers an opportunity for development of diagnostic tests for detection of ASD at an early age.

Objectives

To discover metabolic features present in plasma samples that can discriminate children with ASD from typically developing (TD) children. The ultimate goal is to identify and develop blood-based ASD biomarkers that can be validated in larger clinical trials and deployed to guide individualized therapy and treatment.

Methods

Blood plasma was obtained from children aged 4 to 6, 52 with ASD and 30 age-matched TD children. Samples were analyzed using 5 mass spectrometry-based methods designed to orthogonally measure a broad range of metabolites. Univariate, multivariate and machine learning methods were used to develop models to rank the importance of features that could distinguish ASD from TD.

Results

A set of 179 statistically significant features resulting from univariate analysis were used for multivariate modeling. Subsets of these features properly classified the ASD and TD samples in the 61-sample training set with average accuracies of 84% and 86%, and with a maximum accuracy of 81% in an independent 21-sample validation set.

Conclusions

This analysis of blood plasma metabolites resulted in the discovery of biomarkers that may be valuable in the diagnosis of young children with ASD. The results will form the basis for additional discovery and validation research for 1) determining biomarkers to develop diagnostic tests to detect ASD earlier and improve patient outcomes, 2) gaining new insight into the biochemical mechanisms of various subtypes of ASD 3) identifying biomolecular targets for new modes of therapy, and 4) providing the basis for individualized treatment recommendations.     

Impaired Prefrontal Hemodynamic Maturation in Autism and Unaffected Siblings

Background

Dysfunctions of the prefrontal cortex have been previously reported in individuals with autism spectrum disorders (ASD). Previous studies reported that first-degree relatives of individuals with ASD show atypical brain activity during tasks associated with social function. However, developmental changes in prefrontal dysfunction in ASD and genetic influences on the phenomena remain unclear. In the present study, we investigated the change in hemoglobin concentration in the prefrontal cortex as measured with near-infrared spectroscopy, in children and adults with ASD during the letter fluency test. Moreover, to clarify the genetic influences on developmental changes in the prefrontal dysfunction in ASD, unaffected siblings of the ASD participants were also assessed.

Methodology/Principal Findings

Study participants included 27 individuals with high-functioning ASD, age- and IQ-matched 24 healthy non-affected siblings, and 27 unrelated healthy controls aged 5 to 39 years. The relative concentration of hemoglobin ([Hb]) in the prefrontal cortex was measured during the letter fluency task. For children, neither the [oxy-Hb] change during the task nor task performances differed significantly among three groups. For adults, the [oxy-Hb] increases during the task were significantly smaller in the bilateral prefrontal cortex in ASD than those in control subjects, although task performances were similar. In the adult siblings the [oxy-Hb] change was intermediate between those in controls and ASDs.

Conclusion/Significance

Although indirectly due to a cross-sectional design, the results of this study indicate altered age-related change of prefrontal activity during executive processing in ASD. This is a first near-infrared spectroscopy study that implies alteration in the age-related changes of prefrontal activity in ASD and genetic influences on the phenomena.     

Investigating the Autonomic Nervous System Response to Anxiety in Children with Autism Spectrum Disorders

Assessment of anxiety symptoms in autism spectrum disorders (ASD) is a challenging task due to the symptom overlap between the two conditions as well as the difficulties in communication and awareness of emotions in ASD. This motivates the development of a physiological marker of anxiety in ASD that is independent of language and does not require observation of overt behaviour. In this study, we investigated the feasibility of using indicators of autonomic nervous system (ANS) activity for this purpose. Specially, the objectives of the study were to 1) examine whether or not anxiety causes significant measurable changes in indicators of ANS in an ASD population, and 2) characterize the pattern of these changes in ASD. We measured three physiological indicators of the autonomic nervous system response (heart rate, electrodermal activity, and skin temperature) during a baseline (movie watching) and anxiety condition (Stroop task) in a sample of typically developing children (n = 17) and children with ASD (n = 12). The anxiety condition caused significant changes in heart rate and electrodermal activity in both groups, however, a differential pattern of response was found between the two groups. In particular, the ASD group showed elevated heart rate during both baseline and anxiety conditions. Elevated and blunted phasic electrodermal activity were found in the ASD group during baseline and anxiety conditions, respectively. Finally, the ASD group did not show the typical decrease in skin temperature in response to anxiety. These results suggest that 1) signals of the autonomic nervous system may be used as indicators of anxiety in children with ASD, and 2) ASD may be associated with an atypical autonomic response to anxiety that is most consistent with sympathetic over-arousal and parasympathetic under-arousal.     

Prospective,Blinded Exploratory Evaluation of the PlayWisely Program in Children with Autism Spectrum Disorder

The purpose of the study was to explore a low-cost intervention that targets an increasingly common developmental disorder. The study was a blinded, exploratory evaluation of the PlayWisely program on autism symptoms and essential learning foundation skills (attention, recognition, and memory skills) in children with a diagnosis of autism, autism spectrum disorder (ASD), pervasive developmental disorder – not otherwise specified (PDD-NOS), and Asperger syndrome (AS). Eighteen children, 1 to 10 years of age, were evaluated using the Childhood Autism Rating Scale, Second Edition (CARS2); the PlayWisely Interactive Test of Attention, Recognition, and Memory Skills; Autism Treatment Evaluation Checklist (ATEC), and the Modified Checklist for Autism in Toddlers (M-CHAT). There were significant treatment effects for the PlayWisely measure on the Yellow Sets that examine recognition; Purple Sets that examine brain region agility and early memory skills; Blue Sets that examine phonemic awareness and recognition; and for the Total Sets, with a similar trend toward improvement in the Green Sets that examine perception and Red Sets that examine attention. No other measures reached statistical significance. The results suggest that PlayWisely can improve recognition, brain region agility, phonemic awareness, letter recognition, and early memory skills in ASD. It was observed by the parents, coaches, and study investigators that the children who were less than 3 years of age showed improvements in autism symptoms; however, the group was too small to reach statistical significance. Future studies are needed to see if this intervention can mitigate autism symptoms in very young children with ASD.     

Neural basis of self and other representation in autism: an FMRI study of self-face recognition

Background

Autism is a developmental disorder characterized by decreased interest and engagement in social interactions and by enhanced self-focus. While previous theoretical approaches to understanding autism have emphasized social impairments and altered interpersonal interactions, there is a recent shift towards understanding the nature of the representation of the self in individuals with autism spectrum disorders (ASD). Still, the neural mechanisms subserving self-representations in ASD are relatively unexplored.

Methodology/Principal Findings

We used event-related fMRI to investigate brain responsiveness to images of the subjects'' own face and to faces of others. Children with ASD and typically developing (TD) children viewed randomly presented digital morphs between their own face and a gender-matched other face, and made “self/other” judgments. Both groups of children activated a right premotor/prefrontal system when identifying images containing a greater percentage of the self face. However, while TD children showed activation of this system during both self- and other-processing, children with ASD only recruited this system while viewing images containing mostly their own face.

Conclusions/Significance

This functional dissociation between the representation of self versus others points to a potential neural substrate for the characteristic self-focus and decreased social understanding exhibited by these individuals, and suggests that individuals with ASD lack the shared neural representations for self and others that TD children and adults possess and may use to understand others.     

Altered Heavy Metals and Transketolase Found in Autistic Spectrum Disorder

Autism and autism spectrum disorder (ASD) are developmental brain disorders with complex, obscure, and multifactorial etiology. Our recent clinical survey of patient records from ASD children under the age of 6?years and their age-matched controls revealed evidence of abnormal markers of thiol metabolism, as well as a significant alteration in deposition of several heavy metal species, particularly arsenic, mercury, copper, and iron in hair samples between the groups. Altered thiol metabolism from heavy metal toxicity may be responsible for the biochemical alterations in transketolase, and are mechanisms for oxidative stress production, dysautonomia, and abnormal thiamine homeostasis. It is unknown why the particular metals accumulate, but we suspect that children with ASD may have particular trouble excreting thiol-toxic heavy metal species, many of which exist as divalent cations. Accumulation or altered mercury clearance, as well as concomitant oxidative stress, arising from redox-active metal and arsenic toxicity, offers an intriguing component or possible mechanism for oxidative stress-mediated neurodegeneration in ASD patients. Taken together, these factors may be more important to the etiology of this symptomatically diverse disease spectrum and may offer insights into new treatment approaches and avenues of exploration for this devastating and growing disease.     

Functional Connectivity in the First Year of Life in Infants at Risk for Autism Spectrum Disorder: An EEG Study

In the field of autism research, recent work has been devoted to studying both behavioral and neural markers that may aide in early identification of autism spectrum disorder (ASD). These studies have often tested infants who have a significant family history of autism spectrum disorder, given the increased prevalence observed among such infants. In the present study we tested infants at high- and low-risk for ASD (based on having an older sibling diagnosed with the disorder or not) at 6- and 12-months-of-age. We computed intrahemispheric linear coherence between anterior and posterior sites as a measure of neural functional connectivity derived from electroencephalography while the infants were listening to speech sounds. We found that by 12-months-of-age infants at risk for ASD showed reduced functional connectivity compared to low risk infants. Moreover, by 12-months-of-age infants later diagnosed with ASD showed reduced functional connectivity, compared to both infants at low risk for the disorder and infants at high risk who were not later diagnosed with ASD. Significant differences in functional connectivity were also found between low-risk infants and high-risk infants who did not go onto develop ASD. These results demonstrate that reduced functional connectivity appears to be related to genetic vulnerability for ASD. Moreover, they provide further evidence that ASD is broadly characterized by differences in neural integration that emerge during the first year of life.     

A Chinese Mind-Body Exercise Improves Self-Control of Children with Autism: A Randomized Controlled Trial

Self-control problems commonly manifest as temper outbursts and repetitive/rigid/impulsive behaviors, in children with autism spectrum disorders (ASD), which often contributes to learning difficulties and caregiver burden. The present study aims to compare the effect of a traditional Chinese Chan-based mind-body exercise, Nei Yang Gong, with that of the conventional Progressive Muscle Relaxation (PMR) technique in enhancing the self-control of children with ASD. Forty-six age- and IQ-matched ASD children were randomly assigned to receive group training in Nei Yang Gong (experimental group) or PMR (control group) twice per week for four weeks. The participants’ self-control was measured by three neuropsychological tests and parental rating on standardized questionnaires, and the underlying neural mechanism was assessed by the participants’ brain EEG activity during an inhibitory-control task before and after intervention. The results show that the experimental group demonstrated significantly greater improvement in self-control than the control group, which concurs with the parental reports of reduced autistic symptoms and increased control of temper and behaviors. In addition, the experimental group showed enhanced EEG activity in the anterior cingulate cortex, a region that mediates self-control, whereas the PMR group did not. The present findings support the potential application of Chinese Chan-based mind-body exercises as a form of neuropsychological rehabilitation for patients with self-control problems.Chinese Clinical Trial Registry; Registration No.: ChiCTR-TRC-12002561; URL: www.chictr.org.     

Convergent synaptic and circuit substrates underlying autism genetic risks

There has been a surge of diagnosis of autism spectrum disorders （ASD） over the past decade. While large, high powered genome screening studies of children with ASD have identified numerous genetic risk factors, research efforts to understanding how each of these risk factors contributes to the development autism has met with limited success. Revealing the mechanisms by which these genetic risk factors affect brain development and predispose a child to autism requires mechanistic understanding of the neurobiological changes underlying this devastating group of developmental disorders at multifaceted molecular, cellular and system levels. It has been increasingly clear that the normal trajectory of neurodevelopment is compromised in autism, in multiple domains as much as aberrant neuronal production, growth, functional maturation, patterned connectivity, and balanced excitation and inhibition of brain networks. Many autism risk factors identified in humans have been now reconstituted in experimental mouse models to allow mechanistic interrogation of the biological role of the risk gene. Studies utilizing these mouse models have revealed that underlying the enormous heterogeneity of perturbed cellular events, mechanisms directing synaptic and circuit assembly may provide a unifying explanation for the pathophysiological changes and behavioral endophenotypes seen in autism, although synaptic perturbations are far from being the only alterations relevant for ASD. In this review, we discuss synaptic and circuit abnormalities obtained from several prevalent mouse models, particularly those reflecting syndromic forms of ASD that are caused by single gene perturbations. These compiled results reveal that ASD risk genes contribute to proper signaling of the developing gene networks that maintain synaptic and circuit homeostasis, which is fundamental to normal brain development.