title: Focal Scn1a knockdown induces cognitive impairment without seizures.
abstract: Cognitive impairment is a common comorbidity in pediatric epilepsy that can severely affect quality of life. In many cases, antiepileptic treatments fail to improve cognition. Therefore, a fundamental question is whether underlying brain abnormalities may contribute to cognitive impairment through mechanisms independent of seizures. Here, we examined the possible effects on cognition of Nav1.1 down-regulation, a sodium channel principally involved in Dravet syndrome but also implicated in other cognitive disorders, including autism and Alzheimer's disease. Using an siRNA approach to knockdown Nav1.1 selectively in the basal forebrain region, we were able to target a learning and memory network while avoiding the generation of spontaneous seizures. We show that reduction of Nav1.1 expression in the medial septum and diagonal band of Broca leads to a dysregulation of hippocampal oscillations in association with a spatial memory deficit. We propose that the underlying etiology responsible for Dravet syndrome may directly contribute to cognitive impairment in a manner that is independent from seizures.
authors: Department of Neurology, Neuroscience Center at Dartmouth, Geisel School of Medicine at Dartmouth, Hanover, NH03756,USA.
authors: Alex C
authors: AC
authors: Bender
authors: Heather
authors: H
authors: Natola
authors: Christian
authors: C
authors: Ndong
authors: Gregory L
authors: GL
authors: Holmes
authors: Rod C
authors: RC
authors: Scott
authors: Pierre-Pascal
authors: PP
authors: Lenck-Santini
mesh_terms: D000818:Animals; D015153:Blotting, Western; D003072:Cognition Disorders / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology*; D004569:Electroencephalography; D004831:Epilepsies, Myoclonic / Q000150:complications / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D007150:Immunohistochemistry; D008297:Male; D062550:NAV1.1 Voltage-Gated Sodium Channel / Q000096:biosynthesis* / Q000235:genetics; D034741:RNA, Small Interfering; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012640:Seizures / Q000235:genetics
chemical_list: D062550:NAV1.1 Voltage-Gated Sodium Channel; D034741:RNA, Small Interfering; C568250:Scn1a protein, rat