2. Academic Validation
  3. Genetic and functional analyses demonstrate a role for abnormal glycinergic signaling in autism

Genetic and functional analyses demonstrate a role for abnormal glycinergic signaling in autism

  • Mol Psychiatry. 2016 Jul;21(7):936-45. doi: 10.1038/mp.2015.139.
M Pilorge 1 2 3,  C Fassier 1 2 3,  H Le Corronc 1 2 3 4,  A Potey 1 2 3,  J Bai 1 2 3,  S De Gois 1 2 3,  E Delaby 1 2 3,  B Assouline 5,  V Guinchat 5,  F Devillard 6,  R Delorme 7,  G Nygren 8,  M Råstam 8,  J C Meier 9,  S Otani 1 2 3,  H Cheval 1 2 3,  V M James 10 11,  M Topf 10,  T N Dear 12,  C Gillberg 8,  M Leboyer 13 14 15 16,  B Giros 1 2 3 17,  S Gautron 1 2 3,  J Hazan 1 2 3,  R J Harvey 11,  P Legendre 1 2 3,  C Betancur 1 2 3
Affiliations

Affiliations

  • 1 INSERM, U1130, Paris, France.
  • 2 CNRS, UMR 8246, Paris, France.
  • 3 Sorbonne Universités, Université Pierre et Marie Curie Univ Paris 6, Institut de Biologie Paris Seine, Neuroscience Paris Seine, Paris, France.
  • 4 Université d'Angers, Angers, France.
  • 5 Centre Hospitalier Alpes-Isère, Centre Alpin de Diagnostic Précoce de l'Autisme, Saint Egrève, France.
  • 6 Département de Génétique et Procréation, Centre Hospitalier Universitaire Grenoble, Grenoble, France.
  • 7 Department of Child and Adolescent Psychiatry, AP-HP, Robert Debré University Hospital, Paris, France.
  • 8 Gillberg Neuropsychiatry Centre, University of Gothenburg, Gothenburg, Sweden.
  • 9 Technische Universität Braunschweig, Zoological Institute, Braunschweig, Germany.
  • 10 Department of Biological Sciences, Birkbeck College, Institute for Structural and Molecular Biology, London, UK.
  • 11 Department of Pharmacology, UCL School of Pharmacy, London, UK.
  • 12 Leeds Institute of Molecular Medicine, University of Leeds, St. James's University Hospital, Leeds, UK.
  • 13 INSERM U955, Institut Mondor de Recherche Biomédicale, Créteil, France.
  • 14 Department of Psychiatry, AP-HP, Henri Mondor-Albert Chenevier Hospital, Créteil, France.
  • 15 Faculty of Medicine, University Paris-Est Créteil, Créteil, France.
  • 16 Fondation Fondamental, Créteil, France.
  • 17 Douglas Mental Health University Institute, Department of Psychiatry, McGill University, Montreal, QC, Canada.
PMID: 26370147 DOI: 10.1038/mp.2015.139
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 (GLRA2(Δex8-9)). 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 GLRA2(Δex8)(-)(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 GLRA2(Δex8-9) 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.

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