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Diverse Mechanisms Impair Thalamic Circuit Function in a Dravet Syndrome Mouse Model

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dc.contributor.authorStudtmann, Carleighen
dc.contributor.committeechairSwanger, Sharon A.en
dc.contributor.committeememberPoelzing, Stevenen
dc.contributor.committeememberOlsen, Michelle Lynneen
dc.contributor.committeememberWitcher, Marken
dc.contributor.committeememberMukherjee, Konarken
dc.contributor.departmentGraduate Schoolen
dc.date.accessioned2022-04-07T08:00:13Zen
dc.date.available2022-04-07T08:00:13Zen
dc.date.issued2022-04-06en
dc.description.abstractDravet syndrome (DS) is an infantile epileptic encephalopathy that is caused by loss-of-function mutations in the SCN1A gene, which encodes the voltage-gated sodium channel, NaV1.1. Haploinsufficiency of NaV1.1 in DS patients leads to imbalanced excitability across brain circuits, resulting in a broad phenotypic profile including drug-resistant convulsive and non-convulsive (absence) seizures, cognitive impairment, ataxia, and sleep disruption. Dysfunction in the somatosensory corticothalamic (CT) circuit underlies several DS phenotypes including absence seizures and sleep disturbances. Yet, the precise mechanisms underlying somatosensory CT circuit dysfunction in DS remain unclear. Here, we sought to identify the cellular and synaptic mechanisms underlying somatosensory CT circuit dysfunction in a haploinsufficiency DS mouse model. This work reveals that NaV1.1 haploinsufficiency leads to cell-type-specific changes in the excitability of reticular thalamic (nRT), ventral posterolateral (VPL), and ventral posteromedial (VPM) neurons. Further, we identified alterations in both glutamatergic and GABAergic synaptic connectivity within the somatosensory CT circuit in DS mice. These findings introduce glutamatergic neuron dysfunction and synaptic alterations as novel disease mechanisms underlying thalamic circuit dysfunction in DS, providing new targets for therapeutic intervention. In addition, we reveal that VPL and VPM neurons exhibit distinct firing properties in a healthy CT circuit, suggesting they differentially contribute to circuit-wide function in health and dysfunction in disease.en
dc.description.abstractgeneralThe brain is composed of biological circuits made up of excitatory and inhibitory neurons, which are connected through synapses. Proper balance between excitatory and inhibitory activity in these circuits is essential for maintaining healthy brain function. Dravet syndrome (DS) is an infantile-onset epilepsy caused by mutations in the SCN1A gene, which encodes the voltage-gated sodium channel, Nav1.1. Loss of this protein in the brain leads to an imbalance of excitation and inhibition across a variety of brain circuits, resulting in drug-resistant seizures and cognitive, motor, and learning deficits. Disrupted excitability in the somatosensory corticothalamic (CT) circuit specifically leads to non-convulsive seizures and sleep disruption in DS. However, the mechanisms underlying this circuit's dysfunction remain unclear. Revealing these mechanisms is critical for identifying therapeutic targets by which we can correct circuit function. In this work, we used a mouse model of DS to reveal changes in the excitability of three distinct cell populations of the somatosensory CT circuit. Importantly, changes were exhibited in both excitatory and inhibitory thalamic neuron populations. We further identified impairments in the synapses, both excitatory and inhibitory, connecting the somatosensory CT circuit. These cell-type-specific changes in excitability and synaptic connectivity provide novel targets for therapeutic intervention in DS.en
dc.description.degreeDoctor of Philosophyen
dc.format.mediumETDen
dc.identifier.othervt_gsexam:33978en
dc.identifier.urihttp://hdl.handle.net/10919/109577en
dc.language.isoenen
dc.publisherVirginia Techen
dc.rightsIn Copyrighten
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/en
dc.subjectDravet syndromeen
dc.subjectcorticothalamicen
dc.subjectsomatosensoryen
dc.titleDiverse Mechanisms Impair Thalamic Circuit Function in a Dravet Syndrome Mouse Modelen
dc.typeDissertationen
thesis.degree.disciplineTranslational Biology, Medicine and Healthen
thesis.degree.grantorVirginia Polytechnic Institute and State Universityen
thesis.degree.leveldoctoralen
thesis.degree.nameDoctor of Philosophyen

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