Complex Synaptic and Intrinsic Interactions Disrupt Input/Output Functions in the Hippocampus ofScn1bKnock-Out Mice

Abstract

Pathogenic variants inSCN1Bhave been linked to severe developmental epileptic encephalopathies including Dravet syndrome.Scn1bknock-out (KO) mice modelSCN1Bloss-of-function (LOF) disorders, demonstrating seizures, developmental delays, and early death.SCN1Bencodes the protein β1, an ion channel auxiliary subunit that also has roles in cell adhesion, neurite outgrowth, and gene expression. The goal of this project is to better understand of how loss ofScn1balters information processing in the brain, resulting in seizures and associated cognitive dysfunction. Using slice electrophysiology in the CA1 region of the hippocampus from male and femaleScn1bKO mice and wild-type (WT) littermates, we found that processing of physiologically relevant patterned Schaffer collateral (SC) stimulation produces larger, prolonged depolarizations and increased spiking in KO neurons compared with WTs. KO neurons exhibit enhanced intrinsic excitability, firing more action potentials with current injection. Interestingly, SC stimulation produces smaller, more facilitating excitatory and IPSCs in KO pyramidal neurons, but larger postsynaptic potentials (PSPs) with the same stimulation. We also found reduced intrinsic firing of parvalbumin (PV)-expressing interneurons and disrupted recruitment of both parvalbumin-expressing and somatostatin (SST)-expressing interneurons in response to patterned synaptic stimulation. Neuronal information processing relies on the interplay between synaptic properties, intrinsic properties that amplify or suppress incoming synaptic signals, and firing properties that produce cellular output. We found changes at each of these levels inScn1bKO pyramidal neurons, resulting in fundamentally altered cellular information processing in the hippocampus that likely contributes to the complex phenotypes ofSCN1B-linked epileptic encephalopathies.SIGNIFICANCE STATEMENTGenetic developmental epileptic encephalopathies have limited treatment options, in part because of our lack of understanding of how genetic changes result in dysfunction at the cellular and circuit levels.SCN1Bis a gene linked to Dravet syndrome and other developmental epileptic encephalopathies, andScn1bknock-out (KO) mice phenocopy the human disease, allowing us to study underlying neurophysiological changes. Here, we found changes at all levels of neuronal information processing in brains lackingScn1b, including intrinsic excitability, synaptic properties, and synaptic integration, resulting in greatly enhanced input/output functions of the hippocampus. Our study shows that loss ofScn1bresults in a complex array of cellular and network changes that fundamentally alters information processing in the hippocampus.