NaV1.1 haploinsufficiency impairs glutamatergic and GABAergic neuron function in the thalamus

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dc.contributor.authorStudtmann, Carleighen
dc.contributor.authorLadislav, Mareken
dc.contributor.authorTopolski, Mackenzie A.en
dc.contributor.authorSafari, Monaen
dc.contributor.authorSwanger, Sharon A.en
dc.date.accessioned2022-12-16T14:00:55Zen
dc.date.available2022-12-16T14:00:55Zen
dc.date.issued2022-06en
dc.description.abstractThalamocortical network dysfunction contributes to seizures and sleep deficits in Dravet syndrome (DS), an infantile epileptic encephalopathy, but the underlying molecular and cellular mechanisms remain elusive. DS is primarily caused by mutations in the SCN1A gene encoding the voltage-gated sodium channel Na(V)1.1, which is highly expressed in GABAergic reticular thalamus (nRT) neurons as well as glutamatergic thalamocortical neurons. We hypothesized that Na(V)1.1 haploinsufficiency alters somatosensory corticothalamic circuit function through both intrinsic and synaptic mechanisms in nRT and thalamocortical neurons. Using Scn1a heterozygous mice of both sexes aged P25-P30, we discovered reduced excitability of nRT neurons and thalamocortical neurons in the ventral posterolateral (VPL) thalamus, while thalamocortical ventral posteromedial (VPM) neurons exhibited enhanced excitability. Na(V)1.1 haploinsufficiency enhanced GABAergic synaptic input and reduced glutamatergic input to VPL neurons, but not VPM neurons. In addition, glutamatergic input to nRT neurons was reduced in Scn1a heterozygous mice. These findings introduce alterations in glutamatergic synapse function and aberrant glutamatergic neuron excitability in the thalamus as disease mechanisms in DS, which has been widely considered a disease of GABAergic neurons. This work reveals additional complexity that expands current models of thalamic dysfunction in DS and identifies new components of corticothalamic circuitry as potential therapeutic targets.en
dc.description.notesThis work was supported by the National Institutes of Health [NS105804], CURE Epilepsy, Dravet Syndrome Foundation, and Brain Research Foundation.en
dc.description.sponsorshipNational Institutes of Health [NS105804]; CURE Epilepsy, Dravet Syndrome Foundation; Brain Research Foundationen
dc.description.versionPublished versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1016/j.nbd.2022.105672en
dc.identifier.eissn1095-953Xen
dc.identifier.issn0969-9961en
dc.identifier.other105672en
dc.identifier.pmid35219855en
dc.identifier.urihttp://hdl.handle.net/10919/112921en
dc.identifier.volume167en
dc.language.isoenen
dc.publisherAcademic Press Inc Elsevier Scienceen
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectDravet syndromeen
dc.subjectNa(V)1.1en
dc.subjectSCN1Aen
dc.subjectSomatosensory thalamusen
dc.subjectReticular thalamusen
dc.subjectThalamocortical neuronen
dc.subjectGlutamatergicen
dc.subjectGABAergicen
dc.subjectSynaptic transmissionen
dc.subjectExcitabilityen
dc.titleNa<sub>V</sub>1.1 haploinsufficiency impairs glutamatergic and GABAergic neuron function in the thalamusen
dc.title.serialNeurobiology of Diseaseen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten

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Scholarly Works, Fralin Biomedical Research Institute at VTC
Scholarly Works, Biomedical Sciences and Pathobiology
Scholarly Works, Virginia Tech Carilion School of Medicine (VTCSOM)