| Autor: |
Kyle C. A. Wedgwood, Manoj K. Patel, Eric R. Wengert, Ronald P. Gaykema, A. M. Idrissi, Samantha M. Strohm, Ian C. Wenker, Pravin K. Wagley, Payal S. Panchal |
| Rok vydání: |
2021 |
| Předmět: |
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| DOI: |
10.1101/2021.02.05.429987 |
| Popis: |
SCN8Aepileptic encephalopathy is a devastating epilepsy syndrome caused by mutantSCN8Awhich encodes the voltage-gated sodium channel NaV1.6. To date, it is unclear if and how inhibitory interneurons, which express NaV1.6, influence disease pathology. We found that selective expression of the R1872W mutation in somatostatin (SST) interneurons was sufficient to convey susceptibility to audiogenic seizures. SST interneurons from mutant mice were hyperexcitable but hypersensitive to action potential failure via depolarization block under normal and seizure-like conditions. Remarkably, GqDREADD-mediated activation of wild-type SST interneurons resulted in prolonged electrographic seizures and was accompanied by SST hyperexcitability and depolarization block. Aberrantly large persistent sodium currents, a hallmark ofSCN8Amutations, were observed and were found to contribute directly to aberrant SST physiology in computational and pharmacological experiments. These novel findings demonstrate a critical and previously unidentified contribution of SST interneurons to seizure generation not only inSCN8Aencephalopathy, but epilepsy in general. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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