title: Cognitive Deficits Associated with Nav1.1 Alterations: Involvement of Neuronal Firing Dynamics and Oscillations.
abstract: Brain oscillations play a critical role in information processing and may, therefore, be essential to uncovering the mechanisms of cognitive impairment in neurological disease. In Dravet syndrome (DS), a mutation in SCN1A, coding for the voltage-gated sodium channel Nav1.1, is associated with severe cognitive impairment and seizures. While seizure frequency and severity do not correlate with the extent of impairment, the slowing of brain rhythms may be involved. Here we investigate the role of Nav1.1 on brain rhythms and cognition using RNA interference. We demonstrate that knockdown of Nav1.1 impairs fast- and burst-firing properties of neurons in the medial septum in vivo. The proportion of neurons that fired phase-locked to hippocampal theta oscillations was reduced, and medial septal regulation of theta rhythm was disrupted. During a working memory task, this deficit was characterized by a decrease in theta frequency and was negatively correlated with performance. These findings suggest a fundamental role for Nav1.1 in facilitating fast-firing properties in neurons, highlight the importance of precise temporal control of theta frequency for working memory, and imply that Nav1.1 deficits may disrupt information processing in DS via a dysregulation of brain rhythms.
authors.affiliation: Department of Neurology, Geisel School of Medicine at Dartmouth, Lebanon, NH, United States of America.
authors.forename: Alex C
authors.initials: AC
authors.lastname: Bender
authors.affiliation: Department of Physiology & Neurobiology, Geisel School of Medicine at Dartmouth, Lebanon, NH, United States of America.
authors.forename: Bryan W
authors.initials: BW
authors.lastname: Luikart
authors.affiliation: Department of Neurological Sciences, University of Vermont, Burlington, VT, United States of America.|Institut de Neurobiologie de la Méditerranée, INSERM, Marseille, France.
authors.forename: Pierre-Pascal
authors.initials: PP
authors.lastname: Lenck-Santini
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D045744:Cell Line, Tumor; D003072:Cognition Disorders / Q000209:etiology* / Q000235:genetics; D020667:Diagonal Band of Broca / Q000166:cytology / Q000502:physiology; D004195:Disease Models, Animal; D004831:Epilepsies, Myoclonic / Q000235:genetics / Q000523:psychology*; D005822:Genetic Vectors / Q000235:genetics; D006624:Hippocampus / Q000166:cytology* / Q000502:physiology; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D008297:Male; D018782:Maze Learning / Q000502:physiology; D008569:Memory Disorders / Q000209:etiology* / Q000235:genetics; D008570:Memory, Short-Term / Q000502:physiology*; D062550:NAV1.1 Voltage-Gated Sodium Channel / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D009447:Neuroblastoma / Q000473:pathology; D009474:Neurons / Q000502:physiology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020665:Septum of Brain / Q000166:cytology; D013826:Theta Rhythm / Q000502:physiology
chemical_list: D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; C568250:Scn1a protein, rat