Parvalbumin Interneuron Impairment Leads to Synaptic Transmission Deficits and Seizures in SCN8A Epileptic Encephalopathy

• Published in: bioRxiv
• Main Authors: Miralles, Raquel M, Boscia, Alexis R, Kittur, Shrinidhi, Vundela, Shreya R, Wengert, Eric R, Patel, Manoj K
• Format: Journal Article
• Language: English
• Published: United States 07.03.2024
• ISSN: 2692-8205; 2692-8205
• DOI: 10.1101/2024.02.09.579511

epileptic encephalopathy (EE) is a severe epilepsy syndrome resulting from mutations in the voltage-gated sodium channel Na 1.6, encoded by the gene . Na 1.6 is expressed in both excitatory and inhibitory neurons, yet previous studies have primarily focused on the impact mutations 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 Na 1.6. To assess the role of PV interneurons within EE, we used two mouse models harboring patient-derived gain-of-function mutations, , where the mutation N1768D is expressed globally, and -PV, where the mutation R1872W is selectively expressed in PV interneurons. Expression of the R1872W mutation selectively in PV interneurons led to the development of spontaneous seizures in -PV mice and seizure-induced death, decreasing survival compared to wild-type. Electrophysiology studies showed that PV interneurons in and -PV mice were susceptible to depolarization block, a state of action potential failure. and -PV interneurons also exhibited increased persistent sodium current, a hallmark of gain-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 in and -PV interneurons. These data indicate a distinct impairment of synaptic transmission in EE, 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 in EE, leading to unchecked excitation and ultimately resulting in seizures and seizure-induced death.