Parvalbumin Interneuron Impairment Leads to Synaptic Transmission Deficits and Seizures inSCN8AEpileptic Encephalopathy

Abstract

AbstractSCN8Aepileptic encephalopathy (EE) is a severe epilepsy syndrome resulting fromde novomutations in the voltage-gated sodium channel Nav1.6, encoded by the geneSCN8A. Nav1.6 is expressed in both excitatory and inhibitory neurons, yet previous studies have primarily focused on the impactSCN8Amutations have on excitatory neuron function, with limited studies on the importance of inhibitory interneurons to seizure onset and progression. Inhibitory interneurons are critical in balancing network excitability and are known to contribute to the pathophysiology of other epilepsies. Parvalbumin (PV) interneurons are the most prominent inhibitory neuron subtype in the brain, making up about 40% of inhibitory interneurons. Notably, PV interneurons express high levels of Nav1.6. To assess the role of PV interneurons withinSCN8AEE, we used two mouse models harboring patient-derivedSCN8Again-of-function mutations,Scn8aD/+, where theSCN8Amutation N1768D is expressed globally, andScn8aW/+-PV, where theSCN8Amutation R1872W is selectively expressed in PV interneurons. Expression of the R1872WSCN8Amutation selectively in PV interneurons led to the development of spontaneous seizures inScn8aW/+-PV mice and seizure-induced death, decreasing survival compared to wild-type. Electrophysiology studies showed that PV interneurons inScn8aD/+andScn8aW/+-PV mice were susceptible to depolarization block, a state of action potential failure.Scn8aD/+andScn8aW/+-PV interneurons also exhibited increased persistent sodium current, a hallmark ofSCN8Again-of-function mutations that contributes to depolarization block. Evaluation of synaptic connections between PV interneurons and pyramidal cells showed an increase in synaptic transmission failure at high frequencies (80-120Hz) as well as an increase in synaptic latency inScn8aD/+andScn8aW/+-PV interneurons. These data indicate a distinct impairment of synaptic transmission inSCN8AEE, potentially decreasing overall cortical network inhibition. Together, our novel findings indicate that failure of PV interneuron spiking via depolarization block along with frequency-dependent inhibitory synaptic impairment likely elicits an overall reduction in the inhibitory drive inSCN8AEE, leading to unchecked excitation and ultimately resulting in seizures and seizure-induced death.