Dataset Information

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

ABSTRACT: Glycine receptors (GlyRs) containing the ?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 GlyR-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 Glra2-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 GlyR-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.

SUBMITTER: Comhair J

PROVIDER: S-EPMC6196267 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Publications

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

Comhair Joris J Devoght Jens J Morelli Giovanni G Harvey Robert J RJ Briz Victor V Borrie Sarah C SC Bagni Claudia C Rigo Jean-Michel JM Schiffmann Serge N SN Gall David D Brône Bert B Molchanova Svetlana M SM

Frontiers in molecular neuroscience 20181015

Glycine receptors (GlyRs) containing the α2 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 <i>GLRA2</i> are associated with autism spectrum disorder, but the underlying pathophysiology is not described yet. Here, using <i>Glra2</i>-knockout mice, we found a GlyR-dependent effect on neonatal spontaneous activity of dorsal striatum medi ...[more]

PMID: 30374290

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Project description:Slowly varying activity in the striatum, the main Basal Ganglia input structure, is important for the learning and execution of movement sequences. Striatal medium spiny neurons (MSNs) form cell assemblies whose population firing rates vary coherently on slow behaviourally relevant timescales. It has been shown that such activity emerges in a model of a local MSN network but only at realistic connectivities of 10 ~ 20% and only when MSN generated inhibitory post-synaptic potentials (IPSPs) are realistically sized. Here we suggest a reason for this. We investigate how MSN network generated population activity interacts with temporally varying cortical driving activity, as would occur in a behavioural task. We find that at unrealistically high connectivity a stable winners-take-all type regime is found where network activity separates into fixed stimulus dependent regularly firing and quiescent components. In this regime only a small number of population firing rate components interact with cortical stimulus variations. Around 15% connectivity a transition to a more dynamically active regime occurs where all cells constantly switch between activity and quiescence. In this low connectivity regime, MSN population components wander randomly and here too are independent of variations in cortical driving. Only in the transition regime do weak changes in cortical driving interact with many population components so that sequential cell assemblies are reproducibly activated for many hundreds of milliseconds after stimulus onset and peri-stimulus time histograms display strong stimulus and temporal specificity. We show that, remarkably, this activity is maximized at striatally realistic connectivities and IPSP sizes. Thus, we suggest the local MSN network has optimal characteristics - it is neither too stable to respond in a dynamically complex temporally extended way to cortical variations, nor is it too unstable to respond in a consistent repeatable way. Rather, it is optimized to generate stimulus dependent activity patterns for long periods after variations in cortical excitation.

Dataset Information

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

Publications

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

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