Dravet Syndrome (DS) is a childhood epileptic disorder associated with profound cognitive impairments. DS has been associated in 80% of cases with mutations of the gene SCN1A coding for the voltage-gated sodium channel Nav1.1. 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 during which cognitive systems are permanently sensitive to the mutation effects. To approach this question, we have developed a transient model DS using RNA interference of Scn1a 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 the 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 aim 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.
The second aim i s to investigate 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 the septo-hippocampal network is well characterized, which makes it a model of predilection. The possibility that cognitive impairments may be caused by abnormal neuronal processing in addition to seizures would constitute a shift in the approach to DS. 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.
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 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 childhood epilepsy disorders.
|Kleen, Jonathan K; Testorf, Markus E; Roberts, David W et al. (2016) Oscillation Phase Locking and Late ERP Components of Intracranial Hippocampal Recordings Correlate to Patient Performance in a Working Memory Task. Front Hum Neurosci 10:287|
|Bender, Alex C; Luikart, Bryan W; Lenck-Santini, Pierre-Pascal (2016) Cognitive Deficits Associated with Nav1.1 Alterations: Involvement of Neuronal Firing Dynamics and Oscillations. PLoS One 11:e0151538|
|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|
|Richard, Gregory R; Titiz, Ali; Tyler, Anna et al. (2013) Speed modulation of hippocampal theta frequency correlates with spatial memory performance. Hippocampus 23:1269-79|
|Bender, Alex C; Natola, Heather; Ndong, Christian et al. (2013) Focal Scn1a knockdown induces cognitive impairment without seizures. Neurobiol Dis 54:297-307|
|Bender, Alex C; Morse, Richard P; Scott, Rod C et al. (2012) SCN1A mutations in Dravet syndrome: impact of interneuron dysfunction on neural networks and cognitive outcome. Epilepsy Behav 23:177-86|