Authors: Christine S. Cheah | Brian N. Lundstrom | William A. Catterall | John C. Oakley
Source: Journal of Neuroscience (article, 2019-09-19)
Field: Chemistry — Spectroscopy

Impairment of Sharp-Wave Ripples in a Murine Model of Dravet Syndrome Dravet syndrome (DS) is a severe early-onset epilepsy associated with heterozygous loss-of-function mutations in <i>SCN1A</i> Animal models of DS with global <i>Scn1a</i> haploinsufficiency recapitulate the DS phenotype, including seizures, premature death, and impaired spatial memory performance. Spatial memory requires hippocampal sharp-wave ripples (SPW-Rs), which consist of high-frequency field potential oscillations (ripples, 100-260 Hz) superimposed on a slower SPW. Published <i>in vitro</i> electrophysiologic recordings in DS mice demonstrate reduced firing of GABAergic inhibitory neurons, which are essential for the formation of SPW-R complexes. Here, <i>in vivo</i> electrophysiologic recordings of hippocampal local field potential in both male and female mice demonstrate that <i>Scn1a</i> haploinsufficiency slows intrinsic ripple frequency and reduces the rate of SPW-R occurrence. In DS mice, peak ripple-band power is shifted to lower frequencies, average intertrough intervals of individually detected ripples are slower, and the rate of SPW-R generation is reduced, while SPW amplitude remains unaffected. These alterations in SPW-R properties, in combination with published reductions in interneuron function in DS, suggest a direct link between reduced inhibitory neuron excitability and impaired SPW-R function. A simple interconnected, conductance-based <i>in silico</i> interneuron network model was used to determine whether reduced sodium conductance is sufficient to slow ripple frequency, and stimulation with a modeled SPW demonstrates that reduced sodium conductance alone is sufficient to slow oscillatory frequencies. These findings forge a potential mechanistic link between impaired SPW-R generation and <i>Scn1a</i> mutation in DS mice, expanding the set of disorders in which SPW-R dysfunction contributes to impaired memory.<b>SIGNIFICANCE STATEMENT</b> Disruption of sharp-wave ripples, a characteristic hippocampal rhythm coordinated by the precise timing of GABAergic interneurons, impairs spatial learning and memory. Prior <i>in vitro</i> patch-clamp recordings in brain slices from genetic mouse models of Dravet syndrome (DS) reveal reduced sodium current and excitability in GABAergic interneurons but not excitatory cells, suggesting a causal role for impaired interneuron activity in seizures and cognitive impairment. Here, heterozygous <i>Scn1a</i> mutation in DS mice reduces hippocampal sharp-wave ripple occurrence and slows internal ripple frequency <i>in vivo</i> and a simple <i>in silico</i> model demonstrates reduction in interneuron function alone is sufficient to slow model oscillations. Together, these findings provide a plausible pathophysiologic mechanism for <i>Scn1a</i> gene mutation to impair spatial memory. Dravet syndrome ; Neuroscience ; Psychology ; Audiology ; Medicine ; Epilepsy Advanced NMR Techniques and Applications ; Photoreceptor and optogenetics research ; Advanced MRI Techniques and Applications