Genetics studies of autism spectrum disorder (ASD) have identified several risk genes that are key regulators of synaptic plasticity. Indeed, many of the risk genes that have been linked to these ...disorders encode synaptic scaffolding proteins, receptors, cell adhesion molecules or proteins that are involved in chromatin remodelling, transcription, protein synthesis or degradation, or actin cytoskeleton dynamics. Changes in any of these proteins can increase or decrease synaptic strength or number and, ultimately, neuronal connectivity in the brain. In addition, when deleterious mutations occur, inefficient genetic buffering and impaired synaptic homeostasis may increase an individual's risk for ASD.
Autism spectrum disorders (ASD) are a heterogeneous group of neuropsychiatric disorders characterized by problems in social communication, as well as by the presence of restricted interests, ...stereotyped and repetitive behaviours. In the last 40years, genetic studies have provided crucial information on the causes of ASD and its diversity. In this article, I will first review the current knowledge on the genetics of ASD and then suggest three propositions to foster research in this field. Twin and familial studies estimated the heritability of ASD to be 50%. While most of the inherited part of ASD is captured by common variants, our current knowledge on the genetics of ASD comes almost exclusively from the identification of highly penetrant de novo mutations through candidate gene or whole exome/genome sequencing studies. Approximately 10% of patients with ASD, especially those with intellectual disability, are carriers of de novo copy-number (CNV) or single nucleotide variants (SNV) affecting clinically relevant genes for ASD. Given the function of these genes, it was hypothesized that abnormal synaptic plasticity and failure of neuronal/synaptic homeostasis could increase the risk of ASD. In addition to these discoveries, three propositions coming from institutions, researchers and/or communities of patients and families can be made to foster research on ASD: (i) to use more dimensional and quantitative data than diagnostic categories; (ii) to increase data sharing and research on genetic and brain diversity in human populations; (iii) to involve patients and relatives as participants for research. Hopefully, this knowledge will lead to a better diagnosis, care and integration of individuals with ASD.
Les troubles du spectre autistique (TSA) sont un groupe hétérogène de troubles neuropsychiatriques caractérisés par des problèmes de communication sociale, ainsi que par la présence d’intérêts restreints et de comportements stéréotypés et répétitifs. Au cours des 40 dernières années, les études génétiques ont fourni des informations cruciales sur les causes des TSA et leurs diversités. Dans cet article, je vais d’abord examiner les connaissances actuelles sur la génétique des TSA, puis suggérer trois propositions pour encourager la recherche dans ce domaine. Les études familiales et de jumeaux ont permis d’estimer l’héritabilité des TSA à 50 %. Alors que la plupart de la partie héritée des TSA est due à des variants communs, nos connaissances actuelles sur la génétique des TSA vient presque exclusivement de l’identification de mutations de novo très pénétrantes à l’aide d’études de gènes candidats ou de séquençage d’exome/génome entier. Environ 10 % des patients atteints de TSA, en particulier ceux qui ont une déficience intellectuelle, sont porteurs de mutations de novo de nombre de copies (CNV) ou de changements de nucléotides (SNV) affectant des gènes cliniquement pertinents pour les TSA. Compte tenu de la fonction de ces gènes, il a été émis l’hypothèse qu’une plasticité synaptique anormale et un défaut de l’homéostasie neuronale/synaptique pourrait augmenter le risque de TSA. En plus de ces découvertes, trois propositions provenant des institutions, des chercheurs et/ou des communautés de patients et des familles peuvent être formulées pour encourager la recherche sur les TSA : (i) utiliser des données plus dimensionnelles et quantitatives que les catégories de diagnostic ; (ii) augmenter le partage des données et la recherche sur la diversité génétique et le cerveau dans les populations humaines ; (iii) impliquer les patients et leurs familles en tant que participants à la recherche. En espérant que cette connaissance conduira à de meilleurs diagnostics, de meilleurs soins et une meilleure intégration des personnes atteintes de TSA.
The autism spectrum disorders (ASD) are characterized by impairments in social interaction and stereotyped behaviors. For the majority of individuals with ASD, the causes of the disorder remain ...unknown; however, in up to 25% of cases, a genetic cause can be identified. Chromosomal rearrangements as well as rare and de novo copy-number variants are present in ∼10-20% of individuals with ASD, compared with 1-2% in the general population and/or unaffected siblings. Rare and de novo coding-sequence mutations affecting neuronal genes have also been identified in ∼5-10% of individuals with ASD. Common variants such as single-nucleotide polymorphisms seem to contribute to ASD susceptibility, but, taken individually, their effects appear to be small. Despite a heterogeneous genetic landscape, the genes implicated thus far-which are involved in chromatin remodeling, metabolism, mRNA translation, and synaptic function-seem to converge in common pathways affecting neuronal and synaptic homeostasis. Animal models developed to study these genes should lead to a better understanding of the diversity of the genetic landscapes of ASD.
Autism spectrum disorder (ASD) encompasses a range of disorders that are characterized by social and communication deficits and repetitive behaviors. For the majority of affected individuals, the ...cause of ASD remains unknown, but in at least 20% of the cases, a genetic cause can be identified. There is currently no cure for ASD; however, results from mouse models indicate that some forms of the disorder could be alleviated even at the adult stage. Genes involved in ASD seem to converge on common pathways altering synaptic homeostasis. We propose, given the clinical heterogeneity of ASD, that specific 'synaptic clinical trials' should be designed and launched with the aim of establishing whether phenotype 'reversals' could also occur in humans.
Our understanding of human disorders that affect higher cognitive functions has greatly advanced in recent decades, and over 20 genes associated with non-syndromic mental retardation have been ...identified during the past 15 years. However, proteins encoded by "cognition genes" have such diverse neurodevelopmental functions that delineating specific pathogenetic pathways still poses a tremendous challenge. In this review, we summarize genetic, epigenetic and environmental contributions to neurodevelopmental alterations that either cause or confer vulnerability to autism, a disease primarily affecting social cognition. Taken together, these results begin to provide a unifying view of complex pathogenetic pathways that are likely to lead to autism spectrum disorders through altered neurite morphology, synaptogenesis and cell migration. This review is part of the INMED/TINS special issue "Nature and nurture in brain development and neurological disorders", based on presentations at the annual INMED/TINS symposium (http://inmednet.com/).
A synaptic trek to autism Bourgeron, Thomas
Current opinion in neurobiology,
04/2009, Letnik:
19, Številka:
2
Journal Article
Recenzirano
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.
Autism, an entirely behavioral diagnosis with no largely understood etiologies and no population-wide biomarkers, contrasts with fragile X syndrome (FXS), a single-gene disorder with definite ...alterations of gene expression and neuronal morphology. Nevertheless, the behavioral overlap between autism and FXS suggests some overlapping mechanisms. Understanding how the single-gene alteration in FXS plays out within complex genetic and neural network processes may suggest targets for autism research and illustrate strategies for relating autism to more singular genetic syndromes.
Social interactions in mice are frequently analysed in genetically modified strains in order to get insight of disorders affecting social interactions such as autism spectrum disorders. Different ...types of social interactions have been described, mostly between females and pups, and between adult males and females. However, we recently showed that social interactions between adult males could also encompass cognitive and motivational features. During social interactions, rodents emit ultrasonic vocalizations (USVs), but it remains unknown if call types are differently used depending of the context and if they are correlated with motivational state. Here, we recorded the calls of adult C57BL/6J male mice in various behavioral conditions, such as social interaction, novelty exploration and restraint stress. We introduced a modulator for the motivational state by comparing males maintained in isolation and males maintained in groups before the experiments. Male mice uttered USVs in all social and non-social situations, and even in a stressful restraint context. They nevertheless emitted the most important number of calls with the largest diversity of call types in social interactions, particularly when showing a high motivation for social contact. For mice maintained in social isolation, the number of calls recorded was positively correlated with the duration of social contacts, and most calls were uttered during contacts between the two mice. This correlation was not observed in mice maintained in groups. These results open the way for a deeper understanding and characterization of acoustic signals associated with social interactions. They can also help evaluating the role of motivational states in the emission of acoustic signals.
Abstract
The bulk of social neuroscience takes a ‘stimulus-brain’ approach, typically comparing brain responses to different types of social stimuli, but most of the time in the absence of direct ...social interaction. Over the last two decades, a growing number of researchers have adopted a ‘brain-to-brain’ approach, exploring similarities between brain patterns across participants as a novel way to gain insight into the social brain. This methodological shift has facilitated the introduction of naturalistic social stimuli into the study design (e.g. movies) and, crucially, has spurred the development of new tools to directly study social interaction, both in controlled experimental settings and in more ecologically valid environments. Specifically, ‘hyperscanning’ setups, which allow the simultaneous recording of brain activity from two or more individuals during social tasks, has gained popularity in recent years. However, currently, there is no agreed-upon approach to carry out such ‘inter-brain connectivity analysis’, resulting in a scattered landscape of analysis techniques. To accommodate a growing demand to standardize analysis approaches in this fast-growing research field, we have developed Hyperscanning Python Pipeline, a comprehensive and easy open-source software package that allows (social) neuroscientists to carry-out and to interpret inter-brain connectivity analyses.