Skip to main content

Main menu

  • HOME
  • CONTENT
    • Early Release
    • Featured
    • Current Issue
    • Issue Archive
    • Collections
    • Podcast
  • ALERTS
  • FOR AUTHORS
    • Information for Authors
    • Fees
    • Journal Clubs
    • eLetters
    • Submit
  • EDITORIAL BOARD
  • ABOUT
    • Overview
    • Advertise
    • For the Media
    • Rights and Permissions
    • Privacy Policy
    • Feedback
  • SUBSCRIBE

User menu

  • Log in
  • My Cart

Search

  • Advanced search
Journal of Neuroscience
  • Log in
  • My Cart
Journal of Neuroscience

Advanced Search

Submit a Manuscript
  • HOME
  • CONTENT
    • Early Release
    • Featured
    • Current Issue
    • Issue Archive
    • Collections
    • Podcast
  • ALERTS
  • FOR AUTHORS
    • Information for Authors
    • Fees
    • Journal Clubs
    • eLetters
    • Submit
  • EDITORIAL BOARD
  • ABOUT
    • Overview
    • Advertise
    • For the Media
    • Rights and Permissions
    • Privacy Policy
    • Feedback
  • SUBSCRIBE
PreviousNext
Research Articles, Cellular/Molecular

Corticotropin Releasing Factor Mediates KCa3.1 Inhibition, Hyperexcitability, and Seizures in Acquired Epilepsy

Manindra Nath Tiwari, Sandesh Mohan, Yoav Biala, Oded Shor, Felix Benninger and Yoel Yaari
Journal of Neuroscience 27 July 2022, 42 (30) 5843-5859; DOI: https://doi.org/10.1523/JNEUROSCI.2475-21.2022
Manindra Nath Tiwari
1Department of Medical Neurobiology, Institute for Medical Research Israel-Canada, Hebrew University-Hadassah School of Medicine, Jerusalem, Israel 9112102
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Sandesh Mohan
1Department of Medical Neurobiology, Institute for Medical Research Israel-Canada, Hebrew University-Hadassah School of Medicine, Jerusalem, Israel 9112102
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Yoav Biala
1Department of Medical Neurobiology, Institute for Medical Research Israel-Canada, Hebrew University-Hadassah School of Medicine, Jerusalem, Israel 9112102
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Oded Shor
2Felsenstein Medical Research Center, Beilinson Hospital, Petach Tikva, Israel 4941492
4Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel 6997801
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Felix Benninger
2Felsenstein Medical Research Center, Beilinson Hospital, Petach Tikva, Israel 4941492
3Department of Neurology, Rabin Medical Center, Petach Tikva, Israel 49141492
4Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel 6997801
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Felix Benninger
Yoel Yaari
1Department of Medical Neurobiology, Institute for Medical Research Israel-Canada, Hebrew University-Hadassah School of Medicine, Jerusalem, Israel 9112102
  • 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

Temporal lobe epilepsy (TLE), the most common focal seizure disorder in adults, can be instigated in experimental animals by convulsant-induced status epilepticus (SE). Principal hippocampal neurons from SE-experienced epileptic male rats (post-SE neurons) display markedly augmented spike output compared with neurons from nonepileptic animals (non-SE neurons). This enhanced firing results from a cAMP-dependent protein kinase A-mediated inhibition of KCa3.1, a subclass of Ca2+-gated K+ channels generating the slow afterhyperpolarizing Ca2+-gated K+ current (IsAHP). The inhibition of KCa3.1 in post-SE neurons leads to a marked reduction in amplitude of the IsAHP that evolves during repetitive firing, as well as in amplitude of the associated Ca2+-dependent component of the slow afterhyperpolarization potential (KCa-sAHP). Here we show that KCa3.1 inhibition in post-SE neurons is induced by corticotropin releasing factor (CRF) through its Type 1 receptor (CRF1R). Acute application of CRF1R antagonists restores KCa3.1 activity in post-SE neurons, normalizing KCa-sAHP/IsAHP amplitudes and neuronal spike output, without affecting these variables in non-SE neurons. Moreover, pharmacological antagonism of CRF1Rs in vivo reduces the frequency of spontaneous recurrent seizures in post-SE chronically epileptic rats. These findings may provide a new vista for treating TLE.

SIGNIFICANCE STATEMENT Epilepsy, a common neurologic disorder, often develops following a brain insult. Identifying key cellular mechanisms underlying acquired epilepsy is critical for developing effective antiepileptic therapies. In an experimental model of acquired epilepsy, principal hippocampal neurons manifest hyperexcitability because of downregulation of KCa3.1, a subtype of Ca2+-gated K+ ion channels. We show that KCa3.1 downregulation is mediated by corticotropin releasing factor (CRF) acting through its Type 1 receptor (CRF1R). Congruently, acute application of selective CRF1R antagonists restores KCa3.1 channel activity, leading to normalization of neuronal excitability. In the same model, injection of a CRF1R antagonist to epileptic animals markedly decreases the frequency of electrographic seizures. Therefore, targeting CRF1Rs may provide a new strategy in the treatment of acquired epilepsy.

  • channelopathy
  • CRF
  • hippocampus
  • intrinsic excitability
  • KCa3.1
  • temporal lobe epilepsy

SfN exclusive license.

View Full Text

Member Log In

Log in using your username and password

Enter your Journal of Neuroscience username.
Enter the password that accompanies your username.
Forgot your user name or password?

Purchase access

You may purchase access to this article. This will require you to create an account if you don't already have one.
Back to top

In this issue

The Journal of Neuroscience: 42 (30)
Journal of Neuroscience
Vol. 42, Issue 30
27 Jul 2022
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by author
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.
Corticotropin Releasing Factor Mediates KCa3.1 Inhibition, Hyperexcitability, and Seizures in Acquired Epilepsy
(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.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Print
View Full Page PDF
Citation Tools
Corticotropin Releasing Factor Mediates KCa3.1 Inhibition, Hyperexcitability, and Seizures in Acquired Epilepsy
Manindra Nath Tiwari, Sandesh Mohan, Yoav Biala, Oded Shor, Felix Benninger, Yoel Yaari
Journal of Neuroscience 27 July 2022, 42 (30) 5843-5859; DOI: 10.1523/JNEUROSCI.2475-21.2022

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
Corticotropin Releasing Factor Mediates KCa3.1 Inhibition, Hyperexcitability, and Seizures in Acquired Epilepsy
Manindra Nath Tiwari, Sandesh Mohan, Yoav Biala, Oded Shor, Felix Benninger, Yoel Yaari
Journal of Neuroscience 27 July 2022, 42 (30) 5843-5859; DOI: 10.1523/JNEUROSCI.2475-21.2022
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
  • CRF
  • hippocampus
  • intrinsic excitability
  • KCa3.1
  • temporal lobe epilepsy

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

  • p140Cap regulates the composition and localization of the NMDAR complex in synaptic lipid rafts
  • Crossed corticostriatal projections in the macaque brain
  • Hypothalamic Control of Forelimb Motor Adaptation
Show more Research Articles

Cellular/Molecular

  • p140Cap regulates the composition and localization of the NMDAR complex in synaptic lipid rafts
  • Elevated TNF-α Leads to Neural Circuit Instability in the Absence of Interferon Regulatory Factor 8
  • Neurotensin Release from Dopamine Neurons Drives Long-Term Depression of Substantia Nigra Dopamine Signaling
Show more Cellular/Molecular
  • 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
(JNeurosci logo)
(SfN logo)

Copyright © 2022 by the Society for Neuroscience.
JNeurosci 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.