Abstracts

Rationale: Dravet syndrome (DS) is a rare, debilitating form of genetic epilepsy associated with prolonged seizures, developmental delays, cognitive deficits, and a high rate of mortality. Like many infantile epilepsies, DS has limited treatment options, in part due to our lack of understanding of the cellular and circuit level disruptions that underlie the disorder. DS has been linked to mutations in several genes, including SCN1B, which encodes voltage-gated ion channel auxiliary b1 subunit. The b1 protein associates with and modifies the actions of multiple types of ion channels, including Na_v1.1 and K_v4.2. These channels are vital regulators of action potential initiation and dendritic excitability, respectively.  The Scn1b knockout mouse model phenocopies the human disorder and can be used to study how DS-associated mutations alter neuronal physiology. Previous work has shown that Scn1b knockout mice have hyperexcitable pyramidal neurons, and normal interneuron physiology. Our goal is to understand how changes to intrinsic excitability caused by loss of b1 interact with synapses to integrate inputs and produce subsequent action potential outputs, and thus control neural information processing and the complex phenotypes of DS. Methods: We performed whole cell patch clamp electrophysiological recordings from CA1 pyramidal cells (PCs) in acute hippocampal slices from Scn1b knockout mice and their wild-type (WT) littermates. We used current-clamp recordings to study how neurons in DS integrate their synaptic inputs using various stimulation paradigms of Schaffer collateral axons, activating both excitatory and inhibitory synaptic inputs. Results: We found that stimulation of Schaffer collateral synapses evoked prolonged depolarizations in Scn1b knockout CA1 PCs when compared with WT neurons. Such depolarizations, also called “plateau potentials”, are associated with increased dendritic excitability and plasticity. Coincident with prolonged plateau potentials in Scn1b knockout neurons, we recorded increased frequency of action potential firing in the knockouts compared with control. Finally, we observed an increased occurrence of complex spike formation relative to WT neurons. Conclusions: Here, we report that CA1 PC hyperexcitability is associated with complex changes to synaptic integration and input/output functions in Scn1b knockout neurons. Plateau potentials and complex spikes are vital to nonlinear dendritic synaptic integration and synaptic plasticity. Our data suggest that these processes may be fundamentally altered due to the loss of Scn1b. The b1 protein’s intricate interactions with multiple ion channel families may be a key mechanism by which neurons control cellular processing and plasticity, linking molecular genetic changes caused by loss of b1 with the complex pathophysiology of DS. Funding: Supported by a Junior Investigator Research Award from the American Epilepsy Society.