TY - JOUR
T1 - Impairment of sharp-wave ripples in a murine model of dravet syndrome
AU - Cheah, Christine S.
AU - Lundstrom, Brian N.
AU - Catteral, William A.
AU - Oakley, John C.
N1 - Publisher Copyright:
© 2019 Society for Neuroscience. All rights reserved.
PY - 2019/11/13
Y1 - 2019/11/13
N2 - 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 networkmodel was usedto determine whether reduced sodium conductanceis sufficient to slow ripple frequency, and stimulation with a modeled SPW demonstratesthat reduced sodium conductance alone is sufficientto slow oscillatory frequencies. These findings forge a potential mechanistic link between impaired SPW-R generation and Scn1amutation in DS mice, expanding the set of disorders in which SPW-R dysfunction contributes to impaired memory.
AB - 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 networkmodel was usedto determine whether reduced sodium conductanceis sufficient to slow ripple frequency, and stimulation with a modeled SPW demonstratesthat reduced sodium conductance alone is sufficientto slow oscillatory frequencies. These findings forge a potential mechanistic link between impaired SPW-R generation and Scn1amutation in DS mice, expanding the set of disorders in which SPW-R dysfunction contributes to impaired memory.
KW - Channelopathy
KW - Dravet Syndrome
KW - Epilepsy Comorbidity
KW - Learning And Memory
KW - Scn1A
KW - Sharp-Wave Ripple
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U2 - 10.1523/JNEUROSCI.0890-19.2019
DO - 10.1523/JNEUROSCI.0890-19.2019
M3 - Article
C2 - 31537705
AN - SCOPUS:85074962148
SN - 0270-6474
VL - 39
SP - 9251
EP - 9260
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 46
ER -