Abstract
SCN8A developmental and epileptic encephalopathy (DEE) is a severe epilepsy syndrome caused by de novo mutations in the gene SCN8A, which encodes the voltage-gated sodium channel isoform Nav1.6. Patients with SCN8A DEE experience drug-resistant seizures and are at a higher risk of sudden unexpected death in epilepsy (SUDEP), along with many notable comorbidities such as cognitive and motor dysfunction. Typically, mutations leading to SCN8A DEE are gain-of-function, with loss-of-function mutations most often leading to intellectual disability, developmental delay, or absence seizures. Efficient treatments are limited for patients with SCN8A DEE, although gene therapies targeting the root cause of the disorder are currently in development. Presently, literature in the field of SCN8A DEE suggests that excitatory neuron dysfunction is the primary driver of the disease phenotype. To identify potential new therapeutics, we must further clarify the physiology of this devastating disease. Importantly, key subtypes of inhibitory interneurons have yet to be studied in the context of SCN8A DEE.
In this dissertation thesis, I examine two key subtypes of inhibitory interneurons, parvalbumin-positive (PV) and vasoactive intestinal peptide-positive (VIP) interneurons, and their physiological changes in SCN8A DEE. Using two mouse models with patient-derived SCN8A mutations, I show that SCN8A mutations augment key sodium currents in both PV and VIP interneurons, resulting in changes in their excitability. To uncover a deeper understanding of the SCN8A DEE network, I examined synaptic connections between Scn8a mutant PV interneurons and excitatory pyramidal cells (PCs), indicating that there is an impairment of inhibitory synaptic transmission in SCN8A DEE. Using a Cre-dependent system, I selectively expressed the R1872W SCN8A mutation in both PV and VIP interneurons and show that while this SCN8A mutation selectively in VIP interneurons does not result in seizure susceptibility, it conveys susceptibility to spontaneous seizures when selectively expressed in PV interneurons, a highly unexpected finding. Ultimately, the results presented here provide key contributions to the mechanistic understanding of SCN8A DEE and inhibitory dysfunction in gain-of-function sodium channelopathies.
