Skip to main content
bioRxiv
  • Home
  • About
  • Submit
  • ALERTS / RSS
Advanced Search
New Results

Astrocyte redox dysregulation causes prefrontal hypoactivity: sulforaphane treats non-ictal pathophysiology in ALDH7A1-mediated epilepsy

Travis E. Faust, Wendy Xin, Brian Lee, Amit Agarwal, Sneha Saha, Trexy Palen, Tyler Cash-Padgett, Daniel Wood, Antonello Bonci, Jed W. Fahey, Hanna Jaaro-Peled, Dwight E. Bergles, Akira Sawa
doi: https://doi.org/10.1101/796474
Travis E. Faust
1Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
2Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Wendy Xin
1Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
3Synaptic Plasticity Section, Cellular Neurobiology Branch, National Institute on Drug Abuse Intramural Research Program, Baltimore, MD 21224, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Brian Lee
2Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Amit Agarwal
1Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
4The Chica and Heinz Schaller Research Group, Institute for Anatomy and Cell Biology, Heidelberg University, 69120 Heidelberg, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Sneha Saha
2Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Trexy Palen
2Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Tyler Cash-Padgett
2Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Daniel Wood
2Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Antonello Bonci
1Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
3Synaptic Plasticity Section, Cellular Neurobiology Branch, National Institute on Drug Abuse Intramural Research Program, Baltimore, MD 21224, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jed W. Fahey
5Department of Medicine, Division of Clinical Pharmacology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Hanna Jaaro-Peled
2Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Dwight E. Bergles
1Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
6Johns Hopkins University Kavli Neuroscience Discovery Institute, Baltimore, MD 21205, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Akira Sawa
1Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
2Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
7Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
8McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
9Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: asawa1@jhmi.edu
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Preview PDF
Loading

Abstract

Mutations in the astrocyte-enriched enzyme aldehyde dehydrogenase 7a1 (ALDH7A1) cause a neonatal epilepsy accompanied by treatment-resistant, inter-ictal neuropsychiatric symptoms. Nevertheless, the mechanistic impact of ALDH7A1 dysfunction in the brain remains elusive. We generated ALDH7A1 knockout mice and report that constitutive global ALDH7A1 depletion increases chemoconvulsant sensitivity and altered mood-associated behaviors. However, contrary to our expectation, astrocyte-specific ALDH7A1 depletion only affects mood-associated behaviors. Accordingly, in astrocyte-specific ALDH7A1 knockout mice, we show enhanced redox-sensitive microdomain Ca2+ signaling in astrocytes and both elevated synaptic inhibitory tone and increased dendritic spine density in prelimbic pyramidal neurons. Sulforaphane (SFN), an indirect antioxidant and dietary supplement, has been explored as a possible treatment to ameliorate neuropsychiatric manifestations in autism and schizophrenia, at least at the clinical levels, but its mechanism in the brain is unclear. Here we show that SFN rescues both the physiological and behavioral changes by targeting astrocytic redox imbalance in ALDH7A1 knockout mice, implicating astrocyte redox changes in creating cortical excitatory-inhibitory imbalance and mood alteration.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
Back to top
PreviousNext
Posted October 07, 2019.
Download PDF
Email

Thank you for your interest in spreading the word about bioRxiv.

NOTE: Your email address is requested solely to identify you as the sender of this article.

Enter multiple addresses on separate lines or separate them with commas.
Astrocyte redox dysregulation causes prefrontal hypoactivity: sulforaphane treats non-ictal pathophysiology in ALDH7A1-mediated epilepsy
(Your Name) has forwarded a page to you from bioRxiv
(Your Name) thought you would like to see this page from the bioRxiv website.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Share
Astrocyte redox dysregulation causes prefrontal hypoactivity: sulforaphane treats non-ictal pathophysiology in ALDH7A1-mediated epilepsy
Travis E. Faust, Wendy Xin, Brian Lee, Amit Agarwal, Sneha Saha, Trexy Palen, Tyler Cash-Padgett, Daniel Wood, Antonello Bonci, Jed W. Fahey, Hanna Jaaro-Peled, Dwight E. Bergles, Akira Sawa
bioRxiv 796474; doi: https://doi.org/10.1101/796474
Digg logo Reddit logo Twitter logo Facebook logo Google logo LinkedIn logo Mendeley logo
Citation Tools
Astrocyte redox dysregulation causes prefrontal hypoactivity: sulforaphane treats non-ictal pathophysiology in ALDH7A1-mediated epilepsy
Travis E. Faust, Wendy Xin, Brian Lee, Amit Agarwal, Sneha Saha, Trexy Palen, Tyler Cash-Padgett, Daniel Wood, Antonello Bonci, Jed W. Fahey, Hanna Jaaro-Peled, Dwight E. Bergles, Akira Sawa
bioRxiv 796474; doi: https://doi.org/10.1101/796474

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Subject Area

  • Neuroscience
Subject Areas
All Articles
  • Animal Behavior and Cognition (3514)
  • Biochemistry (7371)
  • Bioengineering (5347)
  • Bioinformatics (20328)
  • Biophysics (10048)
  • Cancer Biology (7781)
  • Cell Biology (11353)
  • Clinical Trials (138)
  • Developmental Biology (6454)
  • Ecology (9985)
  • Epidemiology (2065)
  • Evolutionary Biology (13359)
  • Genetics (9375)
  • Genomics (12614)
  • Immunology (7729)
  • Microbiology (19119)
  • Molecular Biology (7478)
  • Neuroscience (41163)
  • Paleontology (301)
  • Pathology (1235)
  • Pharmacology and Toxicology (2142)
  • Physiology (3183)
  • Plant Biology (6882)
  • Scientific Communication and Education (1276)
  • Synthetic Biology (1900)
  • Systems Biology (5329)
  • Zoology (1091)