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Neurochemical Research

, Volume 41, Issue 7, pp 1751–1760 | Cite as

Epigenetic Suppression of GADs Expression is Involved in Temporal Lobe Epilepsy and Pilocarpine-Induced Mice Epilepsy

  • Jin-Gang Wang
  • Qing Cai
  • Jun Zheng
  • Yu-Shu Dong
  • Jin-Jiang Li
  • Jing-Chen Li
  • Guang-Zhi Hao
  • Chao WangEmail author
  • Ju-Lei WangEmail author
Original Paper

Abstract

Recent studies have shown that histone acetylation is involved with the regulation of enzyme glutamate decarboxylases (GADs), including GAD67 and GAD65. Here, we investigated the histone acetylation modifications of GADs in the pathogenesis of epilepsy and explored the therapeutic effect of a novel second-generation histone deacetylase inhibitor (HDACi) JNJ-26481585 in epilepsy animals. We revealed the suppression of GADs protein and mRNA level, and histone hypoacetylation in patients with temporal lobe epilepsy and pilocarpine-induced epilepsy mice model. Double-immunofluorescence also indicated that the hypoacetyl-H3 was located in hippocampal GAD67/GAD65 positive neurons in epilepsy mice. JNJ-26481585 significantly reversed the decrease of the GAD67/GAD65 both protein and mRNA levels, and the histone hypoacetylation of GABAergic neurons in epilepsy mice. Meanwhile, single-cell real-time PCR performed in GFP-GAD67/GAD65 transgenic mice demonstrated that JNJ-26481585 induced increase of GAD67/GAD65 mRNA level in GABAergic neurons. Furthermore, JNJ-26481585 significantly alleviated the epileptic seizures in mice model. Together, our findings demonstrate inhibition of GADs gene via histone acetylation plays an important role in the pathgenesis of epilepsy, and suggest JNJ-26481585 as a promising therapeutic strategy for epilepsy.

Keywords

Epilepsy Histone acetylation HDAC GAD JNJ-26481585 Single-cell PCR 

Notes

Acknowledgments

This study was supported by Grants of the National Natural Science Foundation of China (Nos. 81201005, 81501115).

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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Jin-Gang Wang
    • 1
  • Qing Cai
    • 2
  • Jun Zheng
    • 1
  • Yu-Shu Dong
    • 3
  • Jin-Jiang Li
    • 3
  • Jing-Chen Li
    • 3
  • Guang-Zhi Hao
    • 3
  • Chao Wang
    • 2
    Email author
  • Ju-Lei Wang
    • 2
    Email author
  1. 1.Department of NeurosurgeryThe 463rd Hospital of PLAShenyangPeople’s Republic of China
  2. 2.Department of Neurosurgery and Institute for Functional Brain Disorders, Tangdu HospitalFourth Military Medical UniversityXi’anPeople’s Republic of China
  3. 3.Department of NeurosurgeryGeneral Hospital of Shenyang Military Command AreaShenyangPeople’s Republic of China

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