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The Journal of Neuroscience, May 30, 2007, 27(22):5967-5975; doi:10.1523/JNEUROSCI.0110-07.2007

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Development/Plasticity/Repair
Epigenetic Modulation of Seizure-Induced Neurogenesis and Cognitive Decline

Sebastian Jessberger,¹ Kinichi Nakashima,⁴ Gregory D. Clemenson, Jr,¹ Eunice Mejia,¹ Emily Mathews,¹ Kerstin Ure,² Shiori Ogawa,³ Christopher M. Sinton,³ Fred H. Gage,¹ and Jenny Hsieh²

¹Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, California 92037, ²Department of Molecular Biology, Cecil H. and Ida Green Center for Reproductive Biology Sciences and ³Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, and ⁴Laboratory of Molecular Neuroscience, Nara Institute of Science and Technology, Ikoma 630-0101, Japan

Correspondence should be addressed to either of the following: Fred H. Gage, Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, CA 92037, Email: gage{at}salk.edu; or Jenny Hsieh, Department of Molecular Biology, Cecil H. and Ida Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, Email: jenny.hsieh{at}utsouthwestern.edu

The conceptual understanding of hippocampal function has been challenged recently by the finding that new granule cells are born throughout life in the mammalian dentate gyrus (DG). The number of newborn neurons is dynamically regulated by a variety of factors. Kainic acid-induced seizures, a rodent model of human temporal lobe epilepsy, strongly induce the proliferation of DG neurogenic progenitor cells and are also associated with long-term cognitive impairment. We show here that the antiepileptic drug valproic acid (VPA) potently blocked seizure-induced neurogenesis, an effect that appeared to be mainly mediated by inhibiting histone deacetylases (HDAC) and normalizing HDAC-dependent gene expression within the epileptic dentate area. Strikingly, the inhibition of aberrant neurogenesis protected the animals from seizure-induced cognitive impairment in a hippocampus-dependent learning task. We propose that seizure-generated granule cells have the potential to interfere with hippocampal function and contribute to cognitive impairment caused by epileptic activity within the hippocampal circuitry. Furthermore, our data indicate that the effectiveness of VPA as an antiepileptic drug may be partially explained by the HDAC-dependent inhibition of aberrant neurogenesis induced by seizure activity within the adult hippocampus.

Key words: valproic acid; neurogenesis; hippocampus; seizure; object recognition; learning; histone deacetylase

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Received Jan. 10, 2007; revised April 23, 2007; accepted April 26, 2007.

Correspondence should be addressed to either of the following: Fred H. Gage, Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, CA 92037, Email: gage{at}salk.edu; or Jenny Hsieh, Department of Molecular Biology, Cecil H. and Ida Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, Email: jenny.hsieh{at}utsouthwestern.edu

This article has been cited by other articles:

				S. Jessberger, C. Zhao, N. Toni, G. D. Clemenson Jr, Y. Li, and F. H. Gage Seizure-Associated, Aberrant Neurogenesis in Adult Rats Characterized with Retrovirus-Mediated Cell Labeling J. Neurosci., August 29, 2007; 27(35): 9400 - 9407. [Abstract] [Full Text] [PDF]

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