Voltage gated Sodium channels (Nav) are critical for the initiation and propagation of action potentials. Mutations of the SCN1A gene, which codes for Nav type 1.1 cause Dravet Syndrome (DS), a severe childhood epileptic disorder associated with profound cognitive impairment. SCN1A mutations have also been described in autism and reduced levels of Nav1.1 are observed in various models of Alzheimer disease (AD). Nav1.1 is highly expressed in inhibitory interneurons that, as we defend here not only explains seizures but also cognitive impairments. Interneurons play a critical role in information processing by controlling the timing of action potentials and oscillatory activities. Alterations of such fundamental components of the neuronal circuitry are likely to have profound consequences on neural processing and, therefore cognition. The goal of this proposal is to investigate the physiological mechanisms leading to cognitive impairments and determine if there is a critical period of development where cognitive systems are permanently sensitive to the mutation effects. To approach this question, we have developed a technique to transiently suppress Nav1.1 expression using RNA interference in rats. This procedure induced cognitive impairments without seizures in rats and can be targeted at specific structures and initiated at specific developmental periods. We hypothesize that NaV1.1 deficits will be sufficient to affect neuronal coding, oscillatory activity and cognition. We also hypothesize that there is a critical period during which cognitive development is particularly sensitive to NaV1.1 abnormalities. To test these hypotheses, we will combine in vivo RNA interference, dynamic analysis of electro- encephalographic (EEG) oscillations and single cell electrophysiology (place cells) in rats performing memory tasks. The first part of this project will be to determine if there is a critical period during which NaV1.1 is critical for cognitive development. We will investigate the acute and long-term cognitive outcomes of intraventricular siRNA administration performed at different periods of post-natal development. In the second aim investigates the neural mechanisms by which NaV1.1 reduction induces cognitive impairments. Here, injections will be focused on a specific structure, the septo-hippocampal region, which is the neural substrate of spatial memory in rats. The role of interneurons in the physiological properties of this network is well characterized, making this an ideal network to investigate. The possibility that cognitive impairments may be caused by abnormal neuronal processing in addition to seizures would constitute a paradigm shift in the approach to DS and other childhood epilepsy disorders with poor cognitive outcome. It would suggest that additional treatment strategies focusing on cognitive function, other than traditional antiepileptic drugs may be necessary to recover normal cognitive function in affected children.

Public Health Relevance

This project aims to determine the physiological mechanisms at the origin of the severe cognitive impairments associated to an intractable childhood epileptic disorder called Dravet Syndrome. Although it is assumed that developmental seizures are at the origin of the cognitive impairment, we defend the hypothesis that the sodium channel mutation identified in this syndrome is also directly affecting neural processing, and therefore, cognition. By focusing on information processing and not seizures, this proposal constitutes a shift in the approach to Dravet Syndrome and other disorders with similar sodium channel deficits.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Developmental Brain Disorders Study Section (DBD)
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Whittemore, Vicky R
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Dartmouth College
Schools of Medicine
United States
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Hernan, Amanda E; Alexander, Abigail; Lenck-Santini, Pierre-Pascal et al. (2014) Attention deficit associated with early life interictal spikes in a rat model is improved with ACTH. PLoS One 9:e89812
Hernan, Amanda E; Alexander, Abigail; Jenks, Kyle R et al. (2014) Focal epileptiform activity in the prefrontal cortex is associated with long-term attention and sociability deficits. Neurobiol Dis 63:25-34
Bender, Alex C; Natola, Heather; Ndong, Christian et al. (2013) Focal Scn1a knockdown induces cognitive impairment without seizures. Neurobiol Dis 54:297-307