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The Journal of Neuroscience, November 1, 2006, 26(44):11342-11346; doi:10.1523/JNEUROSCI.3329-06.2006

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Brief Communications
Enhancing GABA_A Receptor 1 Subunit Levels in Hippocampal Dentate Gyrus Inhibits Epilepsy Development in an Animal Model of Temporal Lobe Epilepsy

YogendraSinh H Raol,¹ Ingrid V Lund,² Sabita Bandyopadhyay,⁶ Guojun Zhang,¹ Daniel S Roberts,^6,7 John H Wolfe,^1,2,3,5 Shelley J Russek,⁶ and Amy R Brooks-Kayal^1,2,4,5

¹Division of Neurology, Pediatric Regional Epilepsy Program, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, ²Neuroscience Graduate Group, ³Center for Comparative Medical Genetics, School of Veterinary Medicine, and Departments of ⁴Neurology and ⁵Pediatrics, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, and ⁶Laboratory of Molecular Neurobiology, Department of Pharmacology and Experimental Therapeutics, and ⁷Program in Biomedical Neurosciences, Boston University School of Medicine, Boston, Massachusetts 02118

Correspondence should be addressed to either of the following: Dr. Amy R. Brooks-Kayal, Children's Hospital of Philadelphia, Division of Neurology, Abramson Pediatric Research Center, Room 502, 3615 Civic Center Boulevard, Philadelphia, PA 19104, Email: kayal{at}email.chop.edu; or Dr. Shelley J. Russek, Laboratory of Molecular Neurobiology, Department of Pharmacology, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118, Email: srussek{at}bu.edu

Differential expression of GABA_A receptor (GABR) subunits has been demonstrated in hippocampus from patients and animals with temporal lobe epilepsy (TLE), but whether these changes are important for epileptogenesis remains unknown. Previous studies in the adult rat pilocarpine model of TLE found reduced expression of GABR 1 subunits and increased expression of 4 subunits in dentate gyrus (DG) of epileptic rats compared with controls. To investigate whether this altered subunit expression is a critical determinant of spontaneous seizure development, we used adeno-associated virus type 2 containing the 4 subunit gene (GABRA4) promoter to drive transgene expression in DG after status epilepticus (SE). This novel use of a condition-dependent promoter upregulated after SE successfully increased expression of GABR 1 subunit mRNA and protein in DG at 1–2 weeks after SE. Enhanced 1 expression in DG resulted in a threefold increase in mean seizure-free time after SE and a 60% decrease in the number of rats developing epilepsy (recurrent spontaneous seizures) in the first 4 weeks after SE. These findings provide the first direct evidence that altering GABR subunit expression can affect the development of epilepsy and suggest that 1 subunit levels are important determinants of inhibitory function in hippocampus.

Key words: spontaneous seizures; epilepsy; gene therapy; rat; AAV; GABA

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Received Aug. 2, 2006; revised Sept. 7, 2006; accepted Sept. 25, 2006.

Correspondence should be addressed to either of the following: Dr. Amy R. Brooks-Kayal, Children's Hospital of Philadelphia, Division of Neurology, Abramson Pediatric Research Center, Room 502, 3615 Civic Center Boulevard, Philadelphia, PA 19104, Email: kayal{at}email.chop.edu; or Dr. Shelley J. Russek, Laboratory of Molecular Neurobiology, Department of Pharmacology, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118, Email: srussek{at}bu.edu

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