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Electrophysiological Alterations of Pyramidal Cells and Interneurons of the CA1 Region of the Hippocampus in a Novel Mouse Model of Dravet Syndrome.

Abstract：

:Dravet syndrome is a developmental epileptic encephalopathy caused by pathogenic variation in SCN1A To characterize the pathogenic substitution (p.H939R) of a local individual with Dravet syndrome, fibroblast cells from the individual were reprogrammed to pluripotent stem cells and differentiated into neurons. Sodium currents of these neurons were compared with healthy control induced neurons. A novel Scn1aH939R/+ mouse model was generated with the p.H939R substitution. Immunohistochemistry and electrophysiological experiments were performed on hippocampal slices of Scn1aH939R/+ mice. We found that the sodium currents recorded in the proband-induced neurons were significantly smaller and slower compared to wild type (WT). The resting membrane potential and spike amplitude were significantly depolarized in the proband-induced neurons. Similar differences in resting membrane potential and spike amplitude were observed in the interneurons of the hippocampus of Scn1aH939R/+ mice. The Scn1aH939R/+ mice showed the characteristic features of a Dravet-like phenotype: increased mortality and both spontaneous and heat-induced seizures. Immunohistochemistry showed a reduction in amount of parvalbumin and vesicular acetylcholine transporter in the hippocampus of Scn1aH939R/+ compared to WT mice. Overall, these results underline hyper-excitability of the hippocampal CA1 circuit of this novel mouse model of Dravet syndrome which, under certain conditions, such as temperature, can trigger seizure activity. This hyper-excitability is due to the altered electrophysiological properties of pyramidal neurons and interneurons which are caused by the dysfunction of the sodium channel bearing the p.H939R substitution. This novel Dravet syndrome model also highlights the reduction in acetylcholine and the contribution of pyramidal cells, in addition to interneurons, to network hyper-excitability.

journal_name

Genetics

journal_title

Genetics

authors

Dyment DA,Schock SC,Deloughery K,Tran MH,Ure K,Nutter LMJ,Creighton A,Yuan J,Banderali U,Comas T,Baumann E,Jezierski A,Care4Rare Canada Consortium,.,Boycott KM,Mackenzie AE,Martina M

doi

10.1534/genetics.120.303399

subject

Has Abstract

pub_date

2020-08-01 00:00:00

pages

1055-1066

issue

eissn

0016-6731

issn

1943-2631

pii

genetics.120.303399

journal_volume

215

pub_type

杂志文章

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Electrophysiological Alterations of Pyramidal Cells and Interneurons of the CA1 Region of the Hippocampus in a Novel Mouse Model of Dravet Syndrome.