SAMENTA - Santé Mentale - Addictions

Synaptic Diversity in Autism Spectrum Disorders – SynDivAutism

Submission summary

Autism spectrum disorders (ASD) are a heterogeneous group of pervasive neurodevelopmental disorders affecting 1% of the population. The diagnosis of ASD is based on impairments in reciprocal social communication and stereotyped behaviors. The SynDivAutism project gathers psychiatrist, geneticists and neurobiologists to tackle the genetic and phenotypic heterogeneity of ASD and to identify causes of these disorders. Over the last 15 years, the geneticist and clinician partners (Partner 1-3) of this project have collected clinical and genetic data of more than >1000 families. Partner 1 and 2 identified the first synaptic pathway associated with ASD – the NLGN-NRX-SHANK pathway. This pathway is known for playing a role in synapse formation and in the excitatory-inhibitory balance within the brain, and these findings thus further highlighted the importance of synaptic molecules and pathways in ASD pathophysiology.
During this project, we will analyze the contribution of deleterious mutations in the coding as well as in the regulatory regions of synaptic genes in a large cohort of patients. All the patients and their relatives were already screened for copy-number variants (CNV) using Illumina arrays (> 600 000 SNPs). The sequence variants will be detected by a combination of whole genome sequencing (>30 families), whole exome sequencing (>50 families) and targeted sequencing of synaptic genes (>500 families). Based on this genetic screen, partner 4 will produce induced pluripotent stem cells (iPSC) and neuronal stem cells (NSC) from 10-15 patients and 5-10 controls. Partners 1, 4 and 5 will then analyze the synaptic phenotypes of the iPSC-derived neurons from control individuals and ASD patients. Neuronal-associated defects will be characterized by comparing the morphological and functional properties of cultured neurons from control or ASD patients. Our study will include the analysis of neuritogenesis, synapse maturation and differentiation, and dendritic spine structure and remodeling of differentiated neurons (i.e. cortical glutamatergic neurons) by fluorescence imaging. Electrophysiological recordings of neuronal activity and excitatory synaptic transmission will be performed. Using glutamate uncaging and calcium imaging we will assess alterations in dendritic integration of synaptic inputs. The cells will be also made available for the scientific community in order to analyze phenotypes for which the partners of the project have little or no expertise.
In summary, the data collected by our project — at the clinical, genetic and synaptic levels — will provide (i) an estimation of the prevalence of synaptic mutations (including regulatory regions) in a large cohort of patients with ASD; (ii) the establishment of a well–phenotyped cohort of patients carrying synaptic mutations for deep clinical as well as neurobiological phenotyping; (iii) A first characterization of the neuronal phenotypes in the human neurons carrying deleterious synaptic mutations. Given that there is currently no cure for ASD, and with prevalence close to 1/100, the results obtained by the SynDivAutism project will help to provide the tools necessary to identify knowledge-based treatments.

Project coordination

Thomas BOURGERON (Institut Pasteur - Unité de Génétique humaine et fonctions cognitives)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.


IP Institut Pasteur - Unité de Génétique humaine et fonctions cognitives
APHP Hopital Robert Debré Service de psychiatrie de l'enfant
INSERM INSERM UMR_S 975: Bases moléculaires, traitement et physiopathologie des maladies neurodégénératives
IP Institut Pasteur

Help of the ANR 554,558 euros
Beginning and duration of the scientific project: September 2013 - 42 Months

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