Biophysical characterization and modeling ofSCN1Again-of-function predicts interneuron hyperexcitability and a predisposition to network instability through homeostatic plasticity

Abstract

ABSTRACTSCN1Again-of-function variants are associated with early onset developmental and epileptic encephalopathies (DEEs) that possess distinct clinical features compared to Dravet syndrome caused bySCN1Aloss-of-function. However, it is unclear howSCN1Again-of-function may predispose to cortical hyper-excitability and seizures. Here, we first report the clinical features of a patient carrying ade novo SCN1Avariant (T162I) associated with neonatal-onset DEE, and then characterize the biophysical properties of T162I and three otherSCN1Avariants associated with neonatal-onset or early infantile DEE (I236V, P1345S, R1636Q). In voltage clamp experiments, three variants (T162I, P1345S and R1636Q) exhibited changes in activation and inactivation properties that enhanced window current, consistent with gain-of-function. Dynamic action potential clamp experiments utilising model neurons incorporating Nav1.1. channels supported a gain-of-function mechanism for all four variants. Here, the T162I, I236V, P1345S, and R1636Q variants exhibited higher peak firing rates relative to wild type and the T162I and R1636Q variants produced a hyperpolarized threshold and reduced neuronal rheobase. To explore the impact of these variants upon cortical excitability, we used a spiking network model containing an excitatory pyramidal cell (PC) and parvalbumin positive (PV) interneuron population.SCN1Again-of-function was modeled by enhancing the excitability of PV interneurons and then incorporating three simple forms of homeostatic plasticity that restored pyramidal cell firing rates. We found that homeostatic plasticity mechanisms exerted differential impact upon network function, with changes to PV- to-PC and PC-to-PC synaptic strength predisposing to network instability. Overall, our findings support a role forSCN1Again-of-function and inhibitory interneuron hyperexcitability in early onset DEE. We propose a mechanism through which homeostatic plasticity pathways can predispose to pathological excitatory activity and contribute to phenotypic variability inSCN1Adisorders.