Res Asst Professor University of Michigan Medical School Ann Arbor, Michigan
This abstract is recognized by Partners Against Mortality in Epilepsy for its contribution to improving the understanding of epilepsy-related mortality
Rationale: Patients with Dravet syndrome (DS), a severe developmental and epileptic encephalopathy, have a high risk of sudden unexpected death in epilepsy (SUDEP). A subset of DS patients have homozygous, lose-of-function variants in SCN1B, the gene encoding voltage-gated sodium channel β1/β1b subunits. Scn1b null mice, which mode DS, have severe seizures and 100% mortality by postnatal day (P) 21. While SUDEP mechanisms are not understood, indirect evidence has implicated respiratory and cardiac involvement, including altered neuronal excitability in brainstem neurons, the autonomic nervous system, or cardiac myocytes. Here, we ask whether Scn1b deletion in mice affects the neuronal excitability of the dorsal motor nucleus of vagus nerve located in the medulla. Methods: Fresh transverse brainstem slices (200 μm) were prepared from the medulla of P14-18 Scn1b null or wild-type (WT) mice. Neurons in the dorsal motor nucleus of vagus nerve were identified based on their location and expression of choline acetyltransferase ChAT)-eGFP. Action potentials and firing patterns of neurons in slices were recorded using whole cell patch-clamp recording technique. Results: In slices from Scn1b null mice, repetitive firing in neurons located in the dorsal motor nucleus of the vagus nerve had a significantly higher sensitivity to depolarization-induced block (P< 0.01), higher threshold for initiation of action potentials (P< 0.01), slower maximum rise and decay rates (P< 0.05), wider half-amplitude duration (P< 0.05) and consequently, significantly lower maximum firing frequency (P< 0.01) compared to neurons in slices prepared from WT littermates. In contrast, there were no significant differences in resting membrane potential or peak action potential amplitude between genotypes. Conclusions: Taken together, these data suggest that neurons in the dorsal motor nucleus of the vagus nerve in Scn1b null mice are hypoexcitable compared to neurons in WT littermates. We propose that reduced neuronal excitability in brainstem vagus nucleus may contribute to the high SUDEP risk associated with SCN1B-linked DS. Funding: Please list any funding that was received in support of this abstract.: Supported by NIH grant R37-NS-076752 to LLI.
