Altered excitability of the brainstem vagus nerve dorsal motor nucleus in the Scn1b null mouse model of Dravet Syndrome
Abstract number :
446
Submission category :
1. Basic Mechanisms / 1F. Other
Year :
2020
Submission ID :
2422788
Source :
www.aesnet.org
Presentation date :
12/6/2020 5:16:48 PM
Published date :
Nov 21, 2020, 02:24 AM
Authors :
Yukun Yuan, University of Michigan Medical School; Heather O’Malley - University of Michigan Medical School; Yan Chen - University of Michigan Medical School; Chunling Chen - University of Michigan Medical School; Larassa Robinson-Cooper - Universssssity
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 seazures 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.
Method:
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.
Conclusion:
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:
:Supported by NIH grant R37-NS-076752 to LLI.
Basic Mechanisms