Donepezil increases resistance to induced seizures in a mouse model of Dravet syndrome.
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ABSTRACT:
SUBMITTER: Wong JC
PROVIDER: S-EPMC6689688 | biostudies-literature | 2019 Aug
REPOSITORIES: biostudies-literature
Publications
Donepezil increases resistance to induced seizures in a mouse model of Dravet syndrome.
Wong Jennifer C JC Thelin Jacquelyn T JT Escayg Andrew A
Annals of clinical and translational neurology 20190723 8
De novo loss-of-function mutations in SCN1A are the main cause of Dravet syndrome, a catastrophic encephalopathy characterized by recurrent early-life febrile seizures, a number of other afebrile seizure types that are often refractory to treatment, and behavioral abnormalities including social deficits, motor dysfunction, and cognitive impairment. We previously demonstrated that the reversible acetylcholinesterase inhibitor, Huperzine A, increases seizure resistance in Scn1a mutants. In the pre ...[more]
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Project description:Loss of function in the Scn1a gene leads to a severe epileptic encephalopathy called Dravet syndrome (DS). Reduced excitability in cortical inhibitory neurons is thought to be the major cause of DS seizures. Here, in contrast, we show enhanced excitability in thalamic inhibitory neurons that promotes the non-convulsive seizures that are a prominent yet poorly understood feature of DS. In a mouse model of DS with a loss of function in Scn1a, reticular thalamic cells exhibited abnormally long bursts of firing caused by the downregulation of calcium-activated potassium SK channels. Our study supports a mechanism in which loss of SK activity causes the reticular thalamic neurons to become hyperexcitable and promote non-convulsive seizures in DS. We propose that reduced excitability of inhibitory neurons is not global in DS and that non-GABAergic mechanisms such as SK channels may be important targets for treatment.
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