Journal article
Genetic and functional analyses demonstrate a role for abnormal glycinergic signaling in autism
Molecular Psychiatry, Vol.21(7), pp.936-945
2016
Abstract
Autism spectrum disorder (ASD) is a common neurodevelopmental condition characterized by marked genetic heterogeneity. Recent studies of rare structural and sequence variants have identified hundreds of loci involved in ASD, but our knowledge of the overall genetic architecture and the underlying pathophysiological mechanisms remains incomplete. Glycine receptors (GlyRs) are ligand-gated chloride channels that mediate inhibitory neurotransmission in the adult nervous system but exert an excitatory action in immature neurons. GlyRs containing the α2 subunit are highly expressed in the embryonic brain, where they promote cortical interneuron migration and the generation of excitatory projection neurons. We previously identified a rare microdeletion of the X-linked gene GLRA2, encoding the GlyR α2 subunit, in a boy with autism. The microdeletion removes the terminal exons of the gene (GLRA2Δex8-9). Here, we sequenced 400 males with ASD and identified one de novo missense mutation, p.R153Q, absent from controls. In vitro functional analysis demonstrated that the GLRA2Δex8-9 protein failed to localize to the cell membrane, while the R153Q mutation impaired surface expression and markedly reduced sensitivity to glycine. Very recently, an additional de novo missense mutation (p.N136S) was reported in a boy with ASD, and we show that this mutation also reduced cell-surface expression and glycine sensitivity. Targeted glra2 knockdown in zebrafish induced severe axon-branching defects, rescued by injection of wild type but not GLRA2Δex8-9 or R153Q transcripts, providing further evidence for their loss-of-function effect. Glra2 knockout mice exhibited deficits in object recognition memory and impaired long-term potentiation in the prefrontal cortex. Taken together, these results implicate GLRA2 in non-syndromic ASD, unveil a novel role for GLRA2 in synaptic plasticity and learning and memory, and link altered glycinergic signaling to social and cognitive impairments.
Details
- Title
- Genetic and functional analyses demonstrate a role for abnormal glycinergic signaling in autism
- Authors
- M Pilorge (Author) - INSERM, FranceC Fassier (Author) - INSERM, FranceH Le Corronc (Author) - INSERM, FranceA Potey (Author) - INSERM, FranceJ Bai (Author) - INSERM, FranceS De Gois (Author) - INSERM, FranceE Delaby (Author) - INSERM, FranceB Assouline (Author) - Centre Alpin de Diagnostic Précoce de l'Autisme, FranceV Guinchat (Author) - Centre Alpin de Diagnostic Précoce de l'Autisme, FranceF Devillard (Author) - Centre Hospitalier Universitaire Grenoble, FranceR Delorme (Author) - Robert Debré University Hospital, FranceG Nygren (Author) - University of Gothenburg, SwedenM Rastam (Author) - University of Gothenburg, SwedenJ C Meier (Author) - Zoological Institute, GermanyS Otani (Author) - INSERM, FranceH Cheval (Author) - INSERM, FranceM James (Author) - Institute for Structural and Molecular Biology, United KingdomM Topf (Author) - Institute for Structural and Molecular Biology, United KingdomT N Dear (Author) - University of Leeds, United KingdomC Gillberg (Author) - University of Gothenburg, SwedenM Leboyer (Author) - Institut Mondor de Recherche Biomédicale, FranceB Giros (Author) - INSERM, FranceS Gautron (Author) - INSERM, FranceJ Hazan (Author) - INSERM, FranceRobert J Harvey (Author) - University College London, United KingdomP Legendre (Author) - INSERM, FranceC Betancur (Author) - INSERM, France
- Publication details
- Molecular Psychiatry, Vol.21(7), pp.936-945
- Publisher
- Nature Publishing Group
- DOI
- 10.1038/mp.2015.139
- ISSN
- 1359-4184
- Organisation Unit
- School of Health and Behavioural Sciences - Legacy; Centre for Bioinnovation; University of the Sunshine Coast, Queensland; School of Health and Sport Sciences - Legacy; School of Health
- Language
- English
- Record Identifier
- 99450936602621
- Output Type
- Journal article
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- Biochemistry & Molecular Biology
- Neurosciences
- Psychiatry
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