Complex Synaptic and Intrinsic Interactions Disrupt Input/Output Functions in the Hippocampus of Scn1b Knock-Out Mice.

Pathogenic variants in SCN1B have been linked to severe developmental epileptic encephalopathies including Dravet syndrome. Scn1b knock-out (KO) mice model SCN1B loss-of-function (LOF) disorders, demonstrating seizures, developmental delays, and early death. SCN1B encodes the protein ß1, 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 Scn1b 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 female Scn1b KO 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 in Scn1b KO pyramidal neurons, resulting in fundamentally altered cellular information processing in the hippocampus that likely contributes to the complex phenotypes of SCN1B-linked epileptic encephalopathies.SIGNIFICANCE STATEMENT Genetic 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. SCN1B is a gene linked to Dravet syndrome and other developmental epileptic encephalopathies, and Scn1b knock-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 lacking Scn1b, including intrinsic excitability, synaptic properties, and synaptic integration, resulting in greatly enhanced input/output functions of the hippocampus. Our study shows that loss of Scn1b results in a complex array of cellular and network changes that fundamentally alters information processing in the hippocampus.

Complex synaptic and intrinsic interactions disrupt input/output functions in the hippocampus of Scn1b knockout mice.

Mutations in the SCN1B gene have been linked to severe developmental epileptic encephalopathies including Dravet syndrome. Scn1b k nock o ut (KO) mice model SCN1B loss of function disorders, demonstrating seizures, developmental delays, and early death. SCN1B encodes the protein ß1, 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 ß1 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 female Scn1b KO mice and w ild-type (WT) littermates, we found that processing of physiologically relevant patterned S chaffer c ollateral (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 in Scn1b KO pyramidal neurons, resulting in fundamentally altered information processing in the hippocampus that likely contributes to the complex phenotypes of SCN1B -linked epileptic encephalopathies. Significance statement: Genetic 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. SCN1B is a gene linked to Dravet syndrome and other epileptic encephalopathies, and Scn1b knockout 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 ß1, including intrinsic excitability, synaptic properties, and synaptic integration, resulting in greatly enhanced input/output functions of the hippocampus. Our study shows that loss of ß1 results in a complex array of cellular and network changes that fundamentally alters information processing in the hippocampus.