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

Molecular Psychiatry volume 21, pages 936–945 (2016)Cite this article

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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.

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Acknowledgements

We are grateful to the families for their participation. We thank Marika Nosten-Bertrand and Stéphanie Daumas for advice on behavioral analyses, Joseph D Buxbaum for helpful discussions, Laïla Gasmi for technical help, Guillaume Pezeron and Isabelle Anselme for help with zebrafish in situ hybridization experiments, Annie Munier for technical support at the Flow Cytometry Facility of the Saint-Antoine Research Center (UPMC), the Institute of Biology Paris-Seine Imaging facility, the DNA and cell bank of the Pitié-Salpêtrière Hospital and the Clinical Investigation Center of the Robert Debré Hospital. This work was supported by a NARSAD Independent Investigator Award from the Brain & Behavior Research Foundation to CB, the Foundation for Autism Research, INSERM, CNRS and UPMC. GN and CG were supported by the Swedish Science Council and by the Annmari and Per Ahlqvist Foundation, RJH and TND by the Medical Research Council (G0500833), JCM by the Bundesministerium für Bildung und Forschung BMBF (Era-Net NEURON II CIPRESS), and MT by a Medical Research Council Centenary Award (G0600084), BBSRC (BB/K01692X/1) and the Leverhulme Trust (RPG-2012-519). MP and ED were supported by PhD fellowships from the French Ministry of Research. We gratefully acknowledge the CNV resources provided by the Autism Genome Project consortium, funded by Autism Speaks, the Health Research Board of Ireland, the Medical Research Council, Genome Canada/Ontario Genomics Institute and the Hilibrand Foundation.

Author contributions

MP and CB conceived and designed the study; MP and AP performed sequencing experiments and variant confirmation; ED participated in the genetic analyses; BA, VG, FD, GN, MR, RD, CG and ML participated in subject recruitment and assessment; JCM provided critical reagents and advice; MP and SG performed site-directed mutagenesis; MP and HLC performed the immunohistochemistry; HLC and PL performed the in vitro electrophysiology studies; SDG performed the biotinylation experiments; VMJ, MT and RJH performed molecular modeling; MP, CF and JH performed the zebrafish experiments; TND and RJH generated Glra2 knockout mice; MP performed the behavioral experiments and analyzed the results with CB; HC contributed to mouse breeding and behavioral analyses; JB and SO performed the ex vivo electrophysiology studies; BG provided key facilities and equipment and consulted on the execution and interpretation of the behavioral and electrophysiological studies; CB coordinated the study; MP and CB wrote the manuscript. All authors reviewed and approved the manuscript.

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Author notes

  1. V Guinchat

    Present address: 18Current address: Department of Child and Adolescent Psychiatry, Pitié-Salpêtrière Hospital, Paris, France.,

  2. M Råstam

    Present address: 19Current address: Department of Clinical Sciences, Child and Adolescent Psychiatry, Lund University, Lund, Sweden.,

  3. S Otani

    Present address: 20Current address: Center of Medical Education, Faculty of Health Sciences, Ryotokuji University, Urayasu, Japan.,

  4. T N Dear

    Present address: 21Current address: South Australian Health and Medical Research Institute, Adelaide, SA, Australia.,

  5. S Gautron, J Hazan and R J Harvey: These authors contributed equally to this work.

Authors and Affiliations

  1. INSERM, U1130, Paris, France

    M Pilorge, C Fassier, H Le Corronc, A Potey, J Bai, S De Gois, E Delaby, S Otani, H Cheval, B Giros, S Gautron, J Hazan, P Legendre & C Betancur

  2. CNRS, UMR 8246, Paris, France

    M Pilorge, C Fassier, H Le Corronc, A Potey, J Bai, S De Gois, E Delaby, S Otani, H Cheval, B Giros, S Gautron, J Hazan, P Legendre & C Betancur

  3. Sorbonne Universités, Université Pierre et Marie Curie Univ Paris 6, Institut de Biologie Paris Seine, Neuroscience Paris Seine, Paris, France

    M Pilorge, C Fassier, H Le Corronc, A Potey, J Bai, S De Gois, E Delaby, S Otani, H Cheval, B Giros, S Gautron, J Hazan, P Legendre & C Betancur

  4. Université d'Angers, Angers, France

    H Le Corronc

  5. Centre Hospitalier Alpes-Isère, Centre Alpin de Diagnostic Précoce de l'Autisme, Saint Egrève, France

    B Assouline & V Guinchat

  6. Département de Génétique et Procréation, Centre Hospitalier Universitaire Grenoble, Grenoble, France

    F Devillard

  7. Department of Child and Adolescent Psychiatry, AP-HP, Robert Debré University Hospital, Paris, France

    R Delorme

  8. Gillberg Neuropsychiatry Centre, University of Gothenburg, Gothenburg, Sweden

    G Nygren, M Råstam & C Gillberg

  9. Technische Universität Braunschweig, Zoological Institute, Braunschweig, Germany

    J C Meier

  10. Department of Biological Sciences, Birkbeck College, Institute for Structural and Molecular Biology, London, UK

    V M James & M Topf

  11. Department of Pharmacology, UCL School of Pharmacy, London, UK

    V M James & R J Harvey

  12. Leeds Institute of Molecular Medicine, University of Leeds, St. James's University Hospital, Leeds, UK

    T N Dear

  13. INSERM U955, Institut Mondor de Recherche Biomédicale, Créteil, France

    M Leboyer

  14. Department of Psychiatry, AP-HP, Henri Mondor-Albert Chenevier Hospital, Créteil, France

    M Leboyer

  15. Faculty of Medicine, University Paris-Est Créteil, Créteil, France

    M Leboyer

  16. Fondation Fondamental, Créteil, France

    M Leboyer

  17. Department of Psychiatry, Douglas Mental Health University Institute, McGill University, Montreal, QC, Canada

    B Giros

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  1. M Pilorge
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  2. C Fassier
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  19. T N Dear
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  20. C Gillberg
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Correspondence to C Betancur.

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Pilorge, M., Fassier, C., Le Corronc, H. et al. Genetic and functional analyses demonstrate a role for abnormal glycinergic signaling in autism. Mol Psychiatry 21, 936–945 (2016). https://doi.org/10.1038/mp.2015.139

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