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Author Notes:

Sookyong.koh@emory.edu

Editor: Giuseppe Biagini, University of Modena and Reggio Emilia, ITALY

All relevant data are within the paper.

The authors have declared that no competing interests exist.

The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Subjects:

Research Funding:

This work was funded by the National Institutes of Health, National Institute of Neurological Disorders and Stroke, https://www.ninds.nih.gov/, R01 NS073768 (SK) Investigator.

Keywords:

  • Science & Technology
  • Multidisciplinary Sciences
  • Science & Technology - Other Topics
  • GLUTAMIC-ACID DECARBOXYLASE
  • TEMPORAL-LOBE EPILEPSY
  • MEDIAL GANGLIONIC EMINENCE
  • INDUCED STATUS EPILEPTICUS
  • SEVERE MYOCLONIC EPILEPSY
  • GAMMA-AMINOBUTYRIC-ACID
  • REDUCED SODIUM CURRENT
  • PLASMA GABA LEVELS
  • NEUROPEPTIDE-Y
  • PSYCHIATRIC COMORBIDITY

Enhanced susceptibility to stress and seizures in GAD65 deficient mice

Tools:

Journal Title:

PLoS ONE

Volume:

Volume 13, Number 1

Publisher:

, Pages e0191794-e0191794

Type of Work:

Article | Final Publisher PDF

Abstract:

Reduced gamma-aminobutyric acid (GABA) inhibition has been implicated in both anxiety and epilepsy. GAD65 -/- (NOD/LtJ) mice have significantly decreased basal GABA levels in the brain and a lowered threshold for seizure generation. One fifth of GAD65 -/- mice experienced stress-induced seizures upon exposure to an open field at 4 weeks of age. In each successive week until 8 weeks of age, the latency to seizures decreased with prior seizure experience. 100% of GAD65 -/- mice exhibited stress-induced seizures by the end of 8 weeks. GAD65 -/- mice also exhibited marked impairment in open field exploratory behavior and deficits in spatial learning acquisition on a Barnes maze. Anxiety-like behavior in an open field was observed prior to seizure onset and was predictive of subsequent seizures. Immunohis-tochemical characterization of interneuron subtypes in GAD65 -/- mice showed a selective decrease in GABA and neuropeptide Y (NPY) levels and no change in calbindin (CLB) or calretinin (CLR) immunoreactivity in the hippocampus. Stem cells from the medial ganglionic eminence (MGE) were injected into the hippocampal hilus to restore GABAergic interneurons. One week after transplantation, MGE-transplanted mice demonstrated significant seizure resistance compared to sham surgical controls. The percent area of GFP + MGE graft in the hippocampus correlated significantly with the increase in seizure latency. Our data indicate that impaired GABAergic neurotransmission can cause anxiety-like behavior and stress-induced seizures that can be rescued by MGE stem cell transplantation.

Copyright information:

© 2018 Qi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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