Skip to main content

Umbrella menu

  • SfN.org
  • eNeuro
  • The Journal of Neuroscience
  • Neuronline
  • BrainFacts.org

Main menu

  • HOME
  • CONTENT
    • Early Release
    • Featured
    • Current Issue
    • Issue Archive
    • Collections
  • ALERTS
  • FOR AUTHORS
    • Preparing a Manuscript
    • Submission Guidelines
    • Fees
    • Journal Club
    • eLetters
    • Submit
  • EDITORIAL BOARD
  • ABOUT
    • Overview
    • Subscriptions
    • Advertise
    • For the Media
    • Rights and Permissions
    • Privacy Policy
    • Feedback
  • SfN.org
  • eNeuro
  • The Journal of Neuroscience
  • Neuronline
  • BrainFacts.org

User menu

  • Log in
  • Subscribe
  • My alerts

Search

  • Advanced search
Journal of Neuroscience
  • Log in
  • Subscribe
  • My alerts
Journal of Neuroscience

Advanced Search

Submit a Manuscript
  • HOME
  • CONTENT
    • Early Release
    • Featured
    • Current Issue
    • Issue Archive
    • Collections
  • ALERTS
  • FOR AUTHORS
    • Preparing a Manuscript
    • Submission Guidelines
    • Fees
    • Journal Club
    • eLetters
    • Submit
  • EDITORIAL BOARD
  • ABOUT
    • Overview
    • Subscriptions
    • Advertise
    • For the Media
    • Rights and Permissions
    • Privacy Policy
    • Feedback
PreviousNext
Research Articles, Neurobiology of Disease

Impairment of Sharp-Wave Ripples in a Murine Model of Dravet Syndrome

Christine S. Cheah, Brian N. Lundstrom, William A. Catterall and John C. Oakley
Journal of Neuroscience 13 November 2019, 39 (46) 9251-9260; DOI: https://doi.org/10.1523/JNEUROSCI.0890-19.2019
Christine S. Cheah
1Departments of Neurology,
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Brian N. Lundstrom
3Department of Neurology, Mayo Clinic, Rochester, Minnesota 55905
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
William A. Catterall
2Pharmacology, University of Washington, Seattle, Washington 98195, and
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
John C. Oakley
1Departments of Neurology, 2Pharmacology, University of Washington, Seattle, Washington 98195, and
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF
Loading

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.

  • channelopathy
  • Dravet syndrome
  • epilepsy comorbidity
  • learning and memory
  • Scn1a
  • sharp-wave ripple
View Full Text

Member Log In

Sign in with your SFN login

If you have an SfN.org account and DO NOT know
your username and/or password

If you DO NOT have an SfN membership

Log in through your institution

If your organization uses OpenAthens, you can log in using your OpenAthens username and password. To check if your institution is supported, please see this list. Contact your library for more details.

Pay Per Article - You may access this article (from the computer you are currently using) for 1 day for US$35.00

Regain Access - You can regain access to a recent Pay per Article purchase if your access period has not yet expired.

Back to top

In this issue

The Journal of Neuroscience: 39 (46)
Journal of Neuroscience
Vol. 39, Issue 46
13 Nov 2019
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by author
  • Advertising (PDF)
  • Ed Board (PDF)
Email

Thank you for sharing this Journal of Neuroscience article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
Impairment of Sharp-Wave Ripples in a Murine Model of Dravet Syndrome
(Your Name) has forwarded a page to you from Journal of Neuroscience
(Your Name) thought you would be interested in this article in Journal of Neuroscience.
Print
View Full Page PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Citation Tools
Impairment of Sharp-Wave Ripples in a Murine Model of Dravet Syndrome
Christine S. Cheah, Brian N. Lundstrom, William A. Catterall, John C. Oakley
Journal of Neuroscience 13 November 2019, 39 (46) 9251-9260; DOI: 10.1523/JNEUROSCI.0890-19.2019

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Respond to this article
Request Permissions
Share
Impairment of Sharp-Wave Ripples in a Murine Model of Dravet Syndrome
Christine S. Cheah, Brian N. Lundstrom, William A. Catterall, John C. Oakley
Journal of Neuroscience 13 November 2019, 39 (46) 9251-9260; DOI: 10.1523/JNEUROSCI.0890-19.2019
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Introduction
    • Materials and Methods
    • Results
    • Discussion
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Keywords

  • channelopathy
  • Dravet syndrome
  • epilepsy comorbidity
  • learning and memory
  • Scn1a
  • sharp-wave ripple

Responses to this article

Respond to this article

Jump to comment:

No eLetters have been published for this article.

Related Articles

Cited By...

More in this TOC Section

Research Articles

  • Sensory- and Motor-Related Responses of Layer 1 Neurons in the Mouse Visual Cortex
  • The Claustrum-Prefrontal Cortex Pathway Regulates Impulsive-Like Behavior
  • Exposing Pathological Sensory Predictions in Tinnitus Using Auditory Intensity Deviant Evoked Responses
Show more Research Articles

Neurobiology of Disease

  • Exposing Pathological Sensory Predictions in Tinnitus Using Auditory Intensity Deviant Evoked Responses
  • Neurovascular Coupling under Chronic Stress Is Modified by Altered GABAergic Interneuron Activity
  • Activated CX3CL1/Smad2 signals prevent neuronal loss and Alzheimer's tau pathology-mediated cognitive dysfunction
Show more Neurobiology of Disease
  • Home
  • Alerts
  • Visit Society for Neuroscience on Facebook
  • Follow Society for Neuroscience on Twitter
  • Follow Society for Neuroscience on LinkedIn
  • Visit Society for Neuroscience on Youtube
  • Follow our RSS feeds

Content

  • Early Release
  • Current Issue
  • Issue Archive
  • Collections

Information

  • For Authors
  • For Advertisers
  • For the Media
  • For Subscribers

About

  • About the Journal
  • Editorial Board
  • Privacy Policy
  • Contact
  • Feedback
(JNeurosci logo)
(SfN logo)

Copyright © 2019 by the Society for Neuroscience.
JNeurosci   Print ISSN: 0270-6474   Online ISSN: 1529-2401

The ideas and opinions expressed in JNeurosci do not necessarily reflect those of SfN or the JNeurosci Editorial Board. Publication of an advertisement or other product mention in JNeurosci should not be construed as an endorsement of the manufacturer’s claims. SfN does not assume any responsibility for any injury and/or damage to persons or property arising from or related to any use of any material contained in JNeurosci.