Genetic and functional analyses demonstrate a role for abnormal glycinergic signaling in autism
Résumé
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.
Mots clés
intellectual disability
interneuron
excitatory-inhibitory imbalance
language delay
synaptic plasticity
long term potentiation
mutation screening
sequencing
X chromosome
rare variants
glycinergic signaling
GLRA2
Autism spectrum disorder
repetitive behaviors
social interaction
locomotor activity
rotarod
microarray
deletion
de novo
mutation
glycine receptor
α2 subunit
prefrontal cortex
learning and memory
novel object recognition
Morris water maze
functional analysis
site-directed mutagenesis
whole-cell recording
electrophysiology
immunohistochemistry
biotinylation
loss of function
zebrafish
axon branching
rescue analyses
knock-out mice
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Pilorge Mol Psychiatry 2016.pdf (9.06 Mo)
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Pilorge Mol Psychiatry 2016-supp.pdf (12.15 Mo)
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| Origine | Fichiers produits par l'(les) auteur(s) |
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| Origine | Fichiers produits par l'(les) auteur(s) |
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