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Citation

  • Authors: Bender, A. C., Natola, H., Ndong, C., Holmes, G. L., Scott, R. C., Lenck-Santini, P. P.
  • Year: 2013
  • Journal: Neurobiol Dis 54 297-307
  • Applications: in vivo / siRNA / jetSI 10 mM

Method

JetSI 10 mM reagent was mixed with 80 mM DOPE (dioleoylphosphatidylethanolamine, Sigma Aldrich, St. Louis, MO) and diluted in ethanol to a concentration of 5 mM JetSI/10 mM DOPE. Next, 1.5 ul of JetSI/DOPE solution was combined with siRNA complexes in a glucose solution to a total volume of 50 ul resulting in a final concentration of 6 μM siRNA complexes in a 5% glucose solution. Between 30 and 60 minutes after preparation of the final siRNA solution, 2.5 μl was infused into the MSDB at a rate of 0.2 μl/min. Each rat was injected once per day on four consecutive days

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.

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