Autism-Associated Promoter Variant in MET Impacts Functional and Structural Brain Networks

As genes that confer increased risk for autism spectrum disorder (ASD) are identified, a crucial next step is to determine how these risk factors impact brain structure and function and contribute to disorder heterogeneity. With three converging lines of evidence, we show that a common, functional ASD risk variant in the Met Receptor Tyrosine Kinase (MET) gene is a potent modulator of key social brain circuitry in children and adolescents with and without ASD. MET risk genotype predicted atypical fMRI activation and deactivation patterns to social stimuli (i.e., emotional faces), as well as reduced functional and structural connectivity in temporo-parietal regions known to have high MET expression, particularly within the default mode network. Notably, these effects were more pronounced in individuals with ASD. These findings highlight how genetic stratification may reduce heterogeneity and help elucidate the biological basis of complex neuropsychiatric disorders such as ASD.     

Genetic architecture,epigenetic influence and environment exposure in the pathogenesis of Autism

Autism spectrum disorder(ASD) is a spectral neurodevelopment disorder affecting approximately 1% of the population. ASD is characterized by impairments in reciprocal social interaction, communication deficits and restricted patterns of behavior. Multiple factors, including genetic/genomic, epigenetic/epigenomic and environmental, are thought to be necessary for autism development. Recent reviews have provided further insight into the genetic/genomic basis of ASD. It has long been suspected that epigenetic mechanisms, including DNA methylation, chromatin structures and long non-coding RNAs may play important roles in the pathology of ASD. In addition to genetic/genomic alterations and epigenetic/epigenomic influences, environmental exposures have been widely accepted as an important role in autism etiology, among which immune dysregulation and gastrointestinal microbiota are two prominent ones.     

The discovery and role of ADAM33, a new candidate gene for asthma

Asthma is a complex disorder in which major genetic and environmental factors interact to initiate the disease and propagate it as a chronic relapsing disorder. Until recently, genetic factors implicated in the disease pathogenesis have been restricted to variants in known molecules involved in the inflammatory or remodelling pathways. This review discusses evidence for a new susceptibility gene for asthma, ADAM33, which was identified by positional cloning and shown to be selectively expressed in mesenchymal but not immune or inflammatory cells. ADAM33 belongs to a family of membrane-anchored metalloproteinases that also have fusagenic, adhesion and intracellular signalling properties. ADAM33 might play a key role in predisposing to the reduced lung function characteristic of asthma, possibly by influencing airway wall remodelling.     

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.     

MHC class I in activity-dependent structural and functional plasticity

Members of the major histocompatibility complex (MHC) class I family of proteins are well known for their central role in the adaptive immune system, where they present self and non-self peptides for immune surveillance. Although the brain has been long considered immune privileged, in part because of an apparent lack of neuronal MHC class I, it has since been shown that MHC class I proteins are expressed by normal, uninfected neurons. Moreover, expression of MHC class I is unusually dynamic in the developing and adult brain, and MHC class I levels in neurons can be regulated by endogenous and exogenous electrical activity. Unexpectedly, several recent studies find that MHC class I is required for distinct activity-dependent events during brain development, adult plasticity, and in response to injury. Together, these studies indicate a novel role for MHC class I proteins in translating electrical activity into changes in synaptic strength and neuronal connectivity in vivo.     

Loss of COMMD1 and copper overload disrupt zinc homeostasis and influence an autism-associated pathway at glutamatergic synapses

Recent studies suggest that synaptic pathology in autism spectrum disorder (ASD) might be caused by the disruption of a signaling pathway at excitatory glutamatergic synapses, which can be influenced by environmental factors. Some factors, such as prenatal zinc deficiency, dysfunction of metallothioneins as well as deletion of COMMD1, all affect brain metal-ion homeostasis and have been associated with ASD. Given that COMMD1 regulates copper levels and that copper and zinc have antagonistic properties, here, we followed the idea that copper overload might induce a local zinc deficiency affecting key players of a putative ASD pathway such as ProSAP/Shank proteins as reported before. Our results show that increased copper levels indeed interfere with intracellular zinc concentrations and affect synaptic ProSAP/Shank levels, which similarly are altered by manipulation of copper and zinc levels through overexpression and knockdown of COMMD1. In line with this, acute and prenatal copper overload lead to local zinc deficiencies in mice. Pups exposed to prenatal copper overload furthermore show a reduction in ProSAP/Shank protein levels in the brain as well as a decreased NMDAR subunit 1 concentration. Thus, it might be likely that brain metal ion status influences a distinct pathway in excitatory synapses associated with genetic forms of ASD.     

孤独症谱系障碍的遗传基础与神经机制

孤独症谱系障碍(autism spectrum disorder,ASD)是一种神经精神障碍,主要表现为社会交往障碍、交流障碍以及局限性的兴趣和重复刻板的行为模式三个主要核心症状．本文介绍了ASD的遗传基础和神经机制的最新研究进展．ASD具有较高的遗传率,且ASD个体的5-羟色胺和睾丸激素都较高．神经影像学研究发现,ASD个体的杏仁核、扣带回、梭状回、镜像神经元和前额叶等大脑区域在结构和功能上都与正常发育个体存在差异,但在个别区域激活模式的差异方向上仍存在不一致的地方．此外,功能连接的研究结果也证实了ASD个体连接不良的假设．未来的研究应该更多地着眼于如何利用这些基础研究成果为临床上提出有效的治疗和训练方式．     

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.     

Environmental influence on neurodevelopmental disorders: Potential association of heavy metal exposure and autism

Environmental factors have been severally established to play major roles in the pathogenesis of neurodevelopmental disorders including autism spectrum disorder (ASD). ASD is a neurodevelopmental disorder that is associated with symptoms that reduce the quality of life of affected individuals such as social interaction deficit, cognitive impairment, intellectual disabilities, restricted and repetitive behavioural patterns. ASD pathogenesis has been associated with environmental and genetic factors that alter physiologic processes during development. Here, we review literatures highlighting the environmental impact on neurodevelopmental disorders, and mechanisms by which environmental toxins may influence neurodevelopment. Furthermore, this review discusses reports highlighting neurotoxic metals (specifically, lead, mercury, cadmium, nickel and manganese) as environmental risk factors in the aetiology of ASD. This work, thus suggests that improving the environment could be vital in the management of ASD.     

Autism-associated gene expression in peripheral leucocytes commonly observed between subjects with autism and healthy women having autistic children

Autism spectrum disorder (ASD) is a severe neuropsychiatric disorder which has complex pathobiology with profound influences of genetic factors in its development. Although the numerous autism susceptible genes were identified, the etiology of autism is not fully explained. Using DNA microarray, we examined gene expression profiling in peripheral blood from 21 individuals in each of the four groups; young adults with ASD, age- and gender-matched healthy subjects (ASD control), healthy mothers having children with ASD (asdMO), and asdMO control. There was no blood relationship between ASD and asdMO. Comparing the ASD group with control, 19 genes were found to be significantly changed. These genes were mainly involved in cell morphology, cellular assembly and organization, and nerve system development and function. In addition, the asdMO group possessed a unique gene expression signature shown as significant alterations of protein synthesis despite of their nonautistic diagnostic status. Moreover, an ASD-associated gene expression signature was commonly observed in both individuals with ASD and asdMO. This unique gene expression profiling detected in peripheral leukocytes from affected subjects with ASD and unaffected mothers having ASD children suggest that a genetic predisposition to ASD may be detectable even in peripheral cells. Altered expression of several autism candidate genes such as FMR-1 and MECP2, could be detected in leukocytes. Taken together, these findings suggest that the ASD-associated genes identified in leukocytes are informative to explore the genetic, epigenetic, and environmental background of ASD and might become potential tools to assess the crucial factors related to the clinical onset of the disorder.     

MHC class II proteins and disease: a structural perspective

MHC class II molecules on the surface of antigen-presenting cells display a range of peptides for recognition by the T-cell receptors of CD4+ T helper cells. Therefore, MHC class II molecules are central to effective adaptive immune responses, but conversely, genetic and epidemiological data have implicated these molecules in the pathogenesis of autoimmune diseases. Indeed, the strength of the associations between particular MHC class II alleles and disease render them the main genetic risk factors for autoimmune disorders such as type 1 diabetes. Here, we discuss the insights that the crystal structures of MHC class II molecules provide into the molecular mechanisms by which sequence polymorphisms might contribute to disease susceptibility.     

Cytomegalovirus MHC class I homologues and natural killer cells: an overview

Viruses that establish a persistent infection with their host have evolved numerous strategies to evade the immune system. Consequently, they are useful tools to dissect the complex cellular processes that comprise the immune response. Rapid progress has been made in recent years in defining the role of cellular MHC class I molecules in regulating the response of natural killer (NK) cells. Concomitantly, the roles of the MHC class I homologues encoded by human and mouse cytomegaloviruses in evading or subverting NK cell responses has received considerable interest. This review discusses the results from a number of studies that have pursued the biological function of the viral MHC class I homologues. Based on the evidence from these studies, hypotheses for the possible role of these intriguing molecules are presented.     

Autistic Disorders and Schizophrenia: Related or Remote? An Anatomical Likelihood Estimation

Shared genetic and environmental risk factors have been identified for autistic spectrum disorders (ASD) and schizophrenia. Social interaction, communication, emotion processing, sensorimotor gating and executive function are disrupted in both, stimulating debate about whether these are related conditions. Brain imaging studies constitute an informative and expanding resource to determine whether brain structural phenotype of these disorders is distinct or overlapping. We aimed to synthesize existing datasets characterizing ASD and schizophrenia within a common framework, to quantify their structural similarities. In a novel modification of Anatomical Likelihood Estimation (ALE), 313 foci were extracted from 25 voxel-based studies comprising 660 participants (308 ASD, 352 first-episode schizophrenia) and 801 controls. The results revealed that, compared to controls, lower grey matter volumes within limbic-striato-thalamic circuitry were common to ASD and schizophrenia. Unique features of each disorder included lower grey matter volume in amygdala, caudate, frontal and medial gyrus for schizophrenia and putamen for autism. Thus, in terms of brain volumetrics, ASD and schizophrenia have a clear degree of overlap that may reflect shared etiological mechanisms. However, the distinctive neuroanatomy also mapped in each condition raises the question about how this is arrived in the context of common etiological pressures.     

Maternal immune activation and autism spectrum disorder: interleukin-6 signaling as a key mechanistic pathway

An emerging area of research in autism spectrum disorder (ASD) is the role of prenatal exposure to inflammatory mediators during critical developmental periods. Epidemiological data has highlighted this relationship showing significant correlations between prenatal exposure to pathogens, including influenza, and the occurrence of ASD. Although there has not been a definitive molecular mechanism established, researchers have begun to investigate this relationship as animal models of maternal infection have support- ed epidemiological findings. Several groups utilizing these animal models have found that activation of the maternal immune system, termed maternal immune activation (MIA), and more specifically the exposure of the developing fetus to maternal cytokines precipitate the neurological, immunological and behavioral abnormalities observed in the offspring of these animals. These abnormalities have correlated with clinical findings of immune dysregulation, neurological and behavioral abnormalities in some autistic individuals. Additionally, researchers have observed genetic variations in these models in genes which regulate neurological and immunological development, similar to what is observed clinically in ASD. Altogether, the role of MIA and cytokine dysregulation, as a key mediator in the neuropathological, behavioral and possibly genetic irregularities observed clinically in autism are important factors that warrant further investigation.     

Rational use of mesenchymal stem cells in the treatment of autism spectrum disorders

Autism and autism spectrum disorders(ASD) refer to a range of conditions characterized by impaired social and communication skills and repetitive behaviors caused by different combinations of genetic and environmental influences. Although the pathophysiology underlying ASD is still unclear, recent evidence suggests that immune dysregulation and neuroinflammation play a role in the etiology of ASD. In particular, there is direct evidence supporting a role for maternal immune activation during prenatal life in neurodevelopmental conditions. Currently, the available options of behavioral therapies and pharmacological and supportive nutritional treatments in ASD are only symptomatic. Given the disturbing rise in the incidence of ASD, and the fact that there is no effective pharmacological therapy for ASD, there is an urgent need for new therapeutic options. Mesenchymal stem cells(MSCs) possess immunomodulatory properties that make them relevant to several diseases associated with inflammation and tissue damage. The paracrine regenerative mechanisms of MSCs are also suggested to be therapeutically beneficial for ASD.Thus the underlying pathology in ASD, including immune system dysregulation and inflammation, represent potential targets for MSC therapy. This review willfocus on immune dysfunction in the pathogenesis of ASD and will further discuss the therapeutic potential for MSCs in mediating ASD-related immunological disorders.     

The Effects of Birth Order and Birth Interval on the Phenotypic Expression of Autism Spectrum Disorder

A rise in the prevalence of diagnosed cases of autism spectrum disorder (ASD) has been reported in several studies in recent years. While this rise in ASD prevalence is at least partially related to increased awareness and broadened diagnostic criteria, the role of environmental factors cannot be ruled out, especially considering that the cause of most cases of ASD remains unknown. The study of families with multiple affected children can provide clues about ASD etiology. While the majority of research on ASD multiplex families has focused on identifying genetic anomalies that may underlie the disorder, the study of symptom severity across ASD birth order may provide evidence for environmental factors in ASD. We compared social and cognitive measures of behavior between over 300 first and second affected siblings within multiplex autism families obtained from the Autism Genetic Resource Exchange dataset. Measures included nonverbal IQ assessed with the Ravens Colored Progressive Matrices, verbal IQ assessed with the Peabody Picture Vocabulary Test, and autism severity assessed with the Social Responsiveness Scale (SRS), an instrument established as a quantitative measure of autism. The results indicated that females were more severely impacted by ASD than males, especially first affected siblings. When first and second affected siblings were compared, significant declines in nonverbal and verbal IQ scores were observed. In addition, SRS results demonstrated a significant increase in autism severity between first and second affected siblings consistent with an overall decline in function as indicated by the IQ data. These results remained significant after controlling for the age and sex of the siblings. Surprisingly, the SRS scores were found to only be significant when the age difference between siblings was less than 2 years. These results suggest that some cases of ASD are influenced by a dosage effect involving unknown epigenetic, environmental, and/or immunological factors.     

Quantitative analysis of mouse urine volatiles: in search of MHC-dependent differences

Genes of the major histocompatibility complex (MHC), which play a critical role in immune recognition, influence mating preference and other social behaviors in mice. Training experiments using urine scent from mice differing only in the MHC complex, from MHC class I mutants or from knock-out mice lacking functional MHC class I molecules (beta2m-deficient), suggest that these behavioral effects are mediated by differences in MHC-dependent volatile components. In search for the physical basis of these behavioral studies, we have conducted a comparison of urinary volatiles in three sub-strains of C57BL/6 mice, a beta2m-deficient mutant lacking functional MHC class I expression and two unrelated inbred strains, using the technique of sorptive extraction with polydimethylsiloxan and subsequent analysis by gas chromatography/mass spectrometry. We show (i) that qualitative differences occur between different inbred strains but not in mice with the C57BL/6 background, (ii) that the individual variability in abundance in the same mouse strain is strongly component-dependent, (iii) that C57BL/6 sub-strains obtained from different provenance show a higher fraction of quantitative differences than a sub-strain and its beta2m-mutant obtained from the same source and (iv) that comparison of the spectra of beta2m mice and the corresponding wild type reveals no qualitative differences in close to 200 major and minor components and only minimal differences in a few substances from an ensemble of 69 selected for quantitative analysis. Our data suggest that odor is shaped by ontogenetic, environmental and genetic factors, and the gestalt of this scent may identify a mouse on the individual and population level; but, within the limits of the ensemble of components analysed, the results do not support the notion that functional MHC class I molecules influence the urinary volatile composition.     

The complex genetics in autism spectrum disorders

Autism spectrum disorders(ASD) are a pervasive neurodevelopmental disease characterized by deficits in social interaction and nonverbal communication, as well as restricted interests and stereotypical behavior. Genetic changes/heritability is one of the major contributing factors, and hundreds to thousands of causative and susceptible genes, copy number variants(CNVs), linkage regions, and micro RNAs have been associated with ASD which clearly indicates that ASD is a complex genetic disorder. Here, we will briefly summarize some of the high-confidence genetic changes in ASD and their possible roles in their pathogenesis.     

Systematic Analysis of Protein–Protein and Gene–Environment Interactions to Decipher the Cognitive Mechanisms of Autism Spectrum Disorder

Cellular and Molecular Neurobiology - Autism spectrum disorder (ASD), a heterogeneous neurodevelopmental disorder resulting from both genetic and environmental risk factors, is manifested by...