Cognitive Deficits Associated with Nav1.1 Alterations: Involvement of Neuronal Firing Dynamics and Oscillations

• Published in: PloS one Vol. 11; no. 3; p. e0151538
• Main Authors: Bender, Alex C, Luikart, Bryan W, Lenck-Santini, Pierre-Pascal
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.03.2016; Public Library of Science (PLoS)
• Subjects: Action Potentials - physiology; Animals; Biology and Life Sciences; Brain; Cell Line, Tumor; Coding; Cognition; Cognition Disorders - etiology; Cognition Disorders - genetics; Cognitive ability; Data processing; Diagonal Band of Broca - cytology; Diagonal Band of Broca - physiology; Disease Models, Animal; Epilepsies, Myoclonic - genetics; Epilepsies, Myoclonic - psychology; Firing; Genetic Vectors - genetics; Hippocampus; Hippocampus - cytology; Hippocampus - physiology; Humans; Impairment; Information processing; Laboratory animals; Lentivirus - genetics; Male; Maze Learning - physiology; Medicine and Health Sciences; Memory; Memory Disorders - etiology; Memory Disorders - genetics; Memory, Short-Term - physiology; Mental task performance; Mutation; NAV1.1 Voltage-Gated Sodium Channel - deficiency; NAV1.1 Voltage-Gated Sodium Channel - genetics; NAV1.1 Voltage-Gated Sodium Channel - physiology; Nerve Tissue Proteins - antagonists & inhibitors; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - physiology; Neuroblastoma - pathology; Neurological complications; Neurons; Neurons - physiology; Neurosciences; Oscillations; Rats; Rats, Sprague-Dawley; Research and Analysis Methods; Rhythm; Ribonucleic acid; RNA; RNA Interference; RNA, Small Interfering - genetics; RNA-mediated interference; Rodents; Seizures; Septum; Septum of Brain - cytology; Short term memory; Sodium; Sodium channels (voltage-gated); Theta Rhythm - physiology; Theta rhythms
• DOI: 10.1371/journal.pone.0151538
• ISSN: 1932-6203

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.