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Cited by 110Autism Spectrum Disorder ResearchGenetics and Neurodevelopmental DisordersNeuroscience and Neuropharmacology Research

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

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Pilorge, M, Fassier, C, Le Corronc, H, Potey, A, Bai, J, De Gois, S, Delaby, E, Assouline, B +19 more·2016·Molecular Psychiatry
DOI 10.1038/mp.2015.139PMC PMC5382231
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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 (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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  • Functional disturbances in synaptic effector genes can induce local and systemic network dysfunction even in the absence of large-scale structural abnormalities, making it a critical component of the biological basis of non-syndromic ASD.

    “Functional disturbances in this domain can induce local and systemic network dysfunction even in the absence of large-scale structural abnormalities, making it a critical component of the biological basis of non-syndromic ASD (Pilorge et al., 2016).”

    From Biological hierarchy from genotype to phenotype in syndromic and non-syndromic autism spectrum disorder (2026) · cites this paper as Pilorge et al., 2016

    The Discussion links GLRA2 disruption to a likely excitation–inhibition imbalance in cortical neuronal networks, and the section on Glra2 knockout mice reports impaired prefrontal synaptic plasticity. The paper does not establish systemic network dysfunction or show that these effects occur in the absence of large-scale structural abnormalities. Its findings support a role for altered glycinergic signaling in ASD, but not the full breadth of the claim. (LLM, conf=0.86)

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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., & Betancur, C.
Affiliations
  • Centre National de la Recherche Scientifique (FR)
  • Centre Hospitalier Universitaire de Grenoble (FR)
  • Assistance Publique – Hôpitaux de Paris (FR)
  • University of Gothenburg (SE)
  • Technische Universität Braunschweig (DE)
  • Institute of Structural and Molecular Biology (GB)
  • University of Leeds (GB)
  • Inserm (FR)
  • UCL School of Pharmacy (GB)
ORCID
Venue
Molecular Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2015-09-15
Volume
21
Issue
7
Pages
936-945
ISSN
  • 1359-4184 (ISSN-L)
  • 1476-5578
DOI
10.1038/mp.2015.139
PMC
PMC5382231
OpenAlex
W2204563731
Cited by
110
References
11
Citations by year
2026: 7 · 2025: 8 · 2024: 14 · 2023: 9 · 2022: 14 · 2021: 4 · 2020: 15 · 2019: 5 · 2018: 13 · 2017: 13 · 2016: 7 · 2015: 1
FWCI
6.81
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Psychiatry (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • HAL (submittedVersion, other-oa)
  • Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
  • BIROn (Birkbeck, University of London) (submittedVersion)
  • ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (submittedVersion)
  • UCL Discovery (University College London) (submittedVersion)
  • Lund University Publications (Lund University) (submittedVersion)
Funders
  • Autism Speaks
  • Genome Canada
  • National Alliance for Research on Schizophrenia and Depression
  • Ontario Genomics
  • Ontario Genomics Institute
  • Leverhulme Trust (BB/K01692X/1, RPG-2012-519)
  • Institut National de la Santé et de la Recherche Médicale
  • Bundesministerium für Bildung und Forschung
  • Centre National de la Recherche Scientifique
  • Medical Research Council (G0600084, G0500833, MR/J004049/1)
  • Biotechnology and Biological Sciences Research Council (BB/K01692X/1)
Topics
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
autism spectrum disorder, de novo missense variant, cell surface expression, object recognition memory, long-term potentiation, synaptic plasticity, learning and memory, zebrafish, knockout mice
MeSH terms
Autism Spectrum Disorder, Adolescent, Adult, Animals, Autistic Disorder, Child, Child, Preschool, Glycine, Humans, Male, Mice, Inbred C57BL, Synaptic Transmission, Neuronal Plasticity, Neurons, Zebrafish, Signal Transduction, Long-Term Potentiation, Receptors, Glycine, Mice, Neurogenesis

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