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• W2974434632 endingPage "9260" @default.
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• W2974434632 abstract "Dravet syndrome (DS) is a severe early-onset epilepsy associated with heterozygous loss-of-function mutations in SCN1A . Animal models of DS with global Scn1a 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 in vitro electrophysiologic recordings in DS mice demonstrate reduced firing of GABAergic inhibitory neurons, which are essential for the formation of SPW-R complexes. Here, in vivo electrophysiologic recordings of hippocampal local field potential in both male and female mice demonstrate that Scn1a 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 in silico 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 Scn1a mutation in DS mice, expanding the set of disorders in which SPW-R dysfunction contributes to impaired memory. SIGNIFICANCE STATEMENT Disruption of sharp-wave ripples, a characteristic hippocampal rhythm coordinated by the precise timing of GABAergic interneurons, impairs spatial learning and memory. Prior in vitro 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 Scn1a mutation in DS mice reduces hippocampal sharp-wave ripple occurrence and slows internal ripple frequency in vivo and a simple in silico model demonstrates reduction in interneuron function alone is sufficient to slow model oscillations. Together, these findings provide a plausible pathophysiologic mechanism for Scn1a gene mutation to impair spatial memory." @default.
• W2974434632 created "2019-09-26" @default.
• W2974434632 creator A5009657302 @default.
• W2974434632 creator A5062567256 @default.
• W2974434632 creator A5077007979 @default.
• W2974434632 creator A5078941732 @default.
• W2974434632 date "2019-09-19" @default.
• W2974434632 modified "2023-09-26" @default.
• W2974434632 title "Impairment of Sharp-Wave Ripples in a Murine Model of Dravet Syndrome" @default.
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• W2974434632 doi "https://doi.org/10.1523/jneurosci.0890-19.2019" @default.
• W2974434632 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/6855681" @default.
• W2974434632 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/31537705" @default.
• W2974434632 hasPublicationYear "2019" @default.
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