Complex synaptic and intrinsic interactions disrupt input/output functions in the hippocampus ofScn1bknockout mice

Abstract

AbstractMutations in theSCN1Bgene have been linked to severe developmental epileptic encephalopathies including Dravet syndrome.Scn1bknockout (KO) mice modelSCN1Bloss of function 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 of β1 alters 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 andwild-type (WT) littermates, we found that processing of physiologically relevant patternedSchaffercollateral (SC) stimulation produces larger, prolonged depolarizations and increased spiking in KO neurons compared to WTs. KO neurons exhibit enhanced intrinsic excitability, firing more action potentials with current injection. Interestingly, SC stimulation produces smaller, more facilitating excitatory and inhibitory postsynaptic currents in KO pyramidal neurons, but larger postsynaptic potentials with the same stimulation. We also found reduced intrinsic firing of parvalbumin-expressing interneurons and disrupted recruitment of both parvalbumin- and somatostatin-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 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 due to 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 epileptic encephalopathies, andScn1bknockout 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 lacking β1, including intrinsic excitability, synaptic properties, and synaptic integration, resulting in greatly enhanced input/output functions of the hippocampus. Our study shows that loss of β1 results in a complex array of cellular and network changes that fundamentally alters information processing in the hippocampus.