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

Pilorge, M. et al. (2016) Genetic and functional analyses demonstrate a role for abnormal glycinergic signaling in autism. Molecular Psychiatry, 21(7), pp. 936-945. (doi: 10.1038/mp.2015.139) (PMID:26370147) (PMCID:PMC5382231)

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.

• Item Type: Articles
• Additional Information: 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.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Gillberg, Professor Christopher
• Authors: Pilorge, M., Fassier, C., Le Corronc, H., Potey, A., Bai, J., De Gois, S., Delaby, E., Assouline, B., Guinchat, V., Devillard, F., Delorme, R., Nygren, G., Råstam, M., Meier, J. C., Otani, S., Cheval, H., James, V. M., Topf, M., Dear, T. N., Gillberg, C., Leboyer, M., Giros, B., Gautron, S., Hazan, J., Harvey, R. J., Legendre, P., and Betancur, C.
• College/School: College of Medical Veterinary and Life Sciences > School of Health & Wellbeing > Mental Health and Wellbeing
• Journal Name: Molecular Psychiatry
• Publisher: Springer Nature
• ISSN: 1359-4184
• ISSN (Online): 1476-5578
• Published Online: 15 September 2015