Alpha2-Containing Glycine Receptors Promote Neonatal Spontaneous Activity of Striatal Medium Spiny Neurons and Support Maturation of Glutamatergic Inputs

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State: Public
Version: Final published version
Serval ID
serval:BIB_9ABDE80EE6E3
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Alpha2-Containing Glycine Receptors Promote Neonatal Spontaneous Activity of Striatal Medium Spiny Neurons and Support Maturation of Glutamatergic Inputs
Journal
Frontiers in Molecular Neuroscience
Author(s)
Comhair J., Devoght J., Morelli G., Harvey R.J., Briz V., Borrie S.C., Bagni C., Rigo J.-M., Schiffmann S.N., Gall D., Brône B., Molchanova S.M.
ISSN
1662-5099
Publication state
Published
Issued date
2018
Peer-reviewed
Oui
Volume
11
Pages
380
Language
english
Abstract
Glycine receptors (GlyRs) containing the alpha 2 subunit are highly expressed in the developing brain, where they regulate neuronal migration and maturation, promote spontaneous network activity and subsequent development of synaptic connections. Mutations in GLRA2 are associated with autism spectrum disorder, but the underlying pathophysiology is not described yet. Here, using Glra2-knockout mice, we found a GIyR-dependent effect on neonatal spontaneous activity of dorsal striatum medium spiny neurons (MSNs) and maturation of the incoming glutamatergic innervation. Our data demonstrate that functional GlyRs are highly expressed in MSNs of one-week-old mice, but they do not generate endogenous chloride-mediated tonic or phasic current. Despite of that, knocking out the Glra2 severely affects the shape of action potentials and impairs spontaneous activity and the frequency of miniature AMPA receptor-mediated currents in MSNs. This reduction in spontaneous activity and glutamatergic signaling can attribute to the observed changes in neonatal behavioral phenotypes as seen in ultrasonic vocalizations and righting reflex. In adult G/ra2-knockout animals, the glutamatergic synapses in MSNs remain functionally underdeveloped. The number of glutamatergic synapses and release probability at presynaptic site remain unaffected, but the amount of postsynaptic AMPA receptors is decreased. This deficit is a consequence of impaired development of the neuronal circuitry since acute inhibition of GlyRs by strychnine in adult MSNs does not affect the properties of glutamatergic synapses. Altogether, these results demonstrate that GIyR-mediated signaling supports neonatal spontaneous MSN activity and, in consequence, promotes the functional maturation of glutamatergic synapses on MSNs. The described mechanism might shed light on the pathophysiological mechanisms in GLRA2-linked autism spectrum disorder cases.
Keywords
utism spectrum disorders, dorsal striatum, medium spiny neurons, glycine receptors, spontaneous activity, synaptic development
Web of science
Open Access
Yes
Create date
25/10/2018 12:24
Last modification date
20/08/2019 15:01
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