Hippocampal deletion of NaV1.1 channels in mice causes thermal seizures and cognitive deficit characteristic of Dravet Syndrome.

Abstract

Dravet Syndrome is a severe childhood epileptic disorder caused by haploinsufficiency of the SCN1A gene encoding brain voltage-gated sodium channel NaV1.1. Symptoms include treatment-refractory epilepsy, cognitive impairment, autistic-like behavior, and premature death. The specific loci of NaV1.1 function in the brain that underlie these global deficits remain unknown. Here we specifically deleted Scn1a in the hippocampus using the Cre-Lox method in weanling mice. Local gene deletion caused selective reduction of inhibitory neurotransmission measured in dentate granule cells. Mice with local NaV1.1 reduction had thermally evoked seizures and spatial learning deficits, but they did not have abnormalities of locomotor activity or social interaction. Our results show that local gene deletion in the hippocampus can induce two of the most severe dysfunctions of Dravet Syndrome: Epilepsy and cognitive deficit. Considering these results, the hippocampus may be a potential target for future gene therapy for Dravet Syndrome.

• Authors: Rachael E Stein, Joshua S Kaplan, Jin Li, William A Catterall
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 116 Issue 33 Pg. 16571-16576 (08 13 2019) ISSN: 1091-6490 [Electronic] United States
• PMID: 31346088 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• NAV1.1 Voltage-Gated Sodium Channel
• Receptors, GABA
• Cre recombinase
• Integrases

Topics

• Animals
• Cognitive Dysfunction (complications, pathology, physiopathology)
• Conditioning, Classical
• Dentate Gyrus (metabolism, physiopathology)
• Dependovirus (metabolism)
• Epilepsies, Myoclonic (complications)
• Fear
• Gene Deletion
• Hippocampus (pathology, physiopathology)
• Inhibitory Postsynaptic Potentials
• Integrases (metabolism)
• Interpersonal Relations
• Memory
• Mice
• Mice, Inbred C57BL
• NAV1.1 Voltage-Gated Sodium Channel (genetics)
• Neurons (metabolism)
• Receptors, GABA (metabolism)
• Seizures (complications, pathology, physiopathology)
• Spatial Learning
• Temperature