Enhancing GABA(A) Receptor Alpha 1 Subunit Levels in Hippocampal Dentate Gyrus Inhibits Epilepsy Development in an Animal Model of Temporal Lobe Epilepsy

Overview

Journal J Neurosci

Specialty Neurology

Date 2006 Nov 3

PMID 17079662

Citations 86

Authors

Yogendrasinh H Raol

Ingrid V Lund

Sabita Bandyopadhyay

Guojun Zhang

Daniel S Roberts

John H Wolfe

Shelley J Russek

Amy R Brooks-Kayal

Affiliations

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Abstract

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 alpha1 subunits and increased expression of alpha4 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 alpha4 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 alpha1 subunit mRNA and protein in DG at 1-2 weeks after SE. Enhanced alpha1 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 alpha1 subunit levels are important determinants of inhibitory function in hippocampus.

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References

Fritschy J, Kiener T, Bouilleret V, Loup F . GABAergic neurons and GABA(A)-receptors in temporal lobe epilepsy. Neurochem Int. 1999; 34(5):435-45. DOI: 10.1016/s0197-0186(99)00040-6. View

Brooks-Kayal A, Shumate M, Jin H, Lin D, Rikhter T, Holloway K . Human neuronal gamma-aminobutyric acid(A) receptors: coordinated subunit mRNA expression and functional correlates in individual dentate granule cells. J Neurosci. 1999; 19(19):8312-8. PMC: 6783026. View

Skorupa A, Fisher K, Wilson J, Parente M, Wolfe J . Sustained production of beta-glucuronidase from localized sites after AAV vector gene transfer results in widespread distribution of enzyme and reversal of lysosomal storage lesions in a large volume of brain in mucopolysaccharidosis VII mice. Exp Neurol. 2000; 160(1):17-27. DOI: 10.1006/exnr.1999.7176. View

Xu R, Janson C, Mastakov M, Lawlor P, Young D, Mouravlev A . Quantitative comparison of expression with adeno-associated virus (AAV-2) brain-specific gene cassettes. Gene Ther. 2001; 8(17):1323-32. DOI: 10.1038/sj.gt.3301529. View

Mohler H, Fritschy J, Rudolph U . A new benzodiazepine pharmacology. J Pharmacol Exp Ther. 2001; 300(1):2-8. DOI: 10.1124/jpet.300.1.2. View

Passini M, Lee E, Heuer G, Wolfe J . Distribution of a lysosomal enzyme in the adult brain by axonal transport and by cells of the rostral migratory stream. J Neurosci. 2002; 22(15):6437-46. PMC: 6758166. DOI: 20026665. View

Prasad Alur R, Foley B, Parente M, Tobin D, Heuer G, Avadhani A . Modification of multiple transcriptional regulatory elements in a Moloney murine leukemia virus gene transfer vector circumvents silencing in fibroblast grafts and increases levels of expression of the transferred enzyme. Gene Ther. 2002; 9(17):1146-54. DOI: 10.1038/sj.gt.3301777. View

Haberman R, Samulski R, McCown T . Attenuation of seizures and neuronal death by adeno-associated virus vector galanin expression and secretion. Nat Med. 2003; 9(8):1076-80. DOI: 10.1038/nm901. View

Lin E, Richichi C, Young D, Baer K, Vezzani A, During M . Recombinant AAV-mediated expression of galanin in rat hippocampus suppresses seizure development. Eur J Neurosci. 2003; 18(7):2087-92. DOI: 10.1046/j.1460-9568.2003.02926.x. View

10.

Passini M, Watson D, Wolfe J . Gene delivery to the mouse brain with adeno-associated virus. Methods Mol Biol. 2004; 246:225-36. DOI: 10.1385/1-59259-650-9:225. View

11.

Richichi C, Lin E, Stefanin D, Colella D, Ravizza T, Grignaschi G . Anticonvulsant and antiepileptogenic effects mediated by adeno-associated virus vector neuropeptide Y expression in the rat hippocampus. J Neurosci. 2004; 24(12):3051-9. PMC: 6729841. DOI: 10.1523/JNEUROSCI.4056-03.2004. View

12.

Zhang G, Raol Y, Hsu F, Coulter D, Brooks-Kayal A . Effects of status epilepticus on hippocampal GABAA receptors are age-dependent. Neuroscience. 2004; 125(2):299-303. PMC: 2441871. DOI: 10.1016/j.neuroscience.2004.01.040. View

13.

Seki T, Matsubayashi H, Amano T, Kitada K, Serikawa T, Sasa M . Adenoviral gene transfer of aspartoacylase ameliorates tonic convulsions of spontaneously epileptic rats. Neurochem Int. 2004; 45(1):171-8. DOI: 10.1016/j.neuint.2003.10.009. View

14.

Rosenqvist N, Jakobsson J, Lundberg C . Inhibition of chromatin condensation prevents transgene silencing in a neural progenitor cell line transplanted to the rat brain. Cell Transplant. 2005; 14(2-3):129-38. DOI: 10.3727/000000005783983188. View

15.

Roberts D, Raol Y, Bandyopadhyay S, Lund I, Budreck E, Passini M . Egr3 stimulation of GABRA4 promoter activity as a mechanism for seizure-induced up-regulation of GABA(A) receptor alpha4 subunit expression. Proc Natl Acad Sci U S A. 2005; 102(33):11894-9. PMC: 1187961. DOI: 10.1073/pnas.0501434102. View

16.

McCown T . Adeno-associated virus-mediated expression and constitutive secretion of galanin suppresses limbic seizure activity in vivo. Mol Ther. 2006; 14(1):63-8. DOI: 10.1016/j.ymthe.2006.04.004. View

17.

Roberts D, Hu Y, Lund I, Brooks-Kayal A, Russek S . Brain-derived neurotrophic factor (BDNF)-induced synthesis of early growth response factor 3 (Egr3) controls the levels of type A GABA receptor alpha 4 subunits in hippocampal neurons. J Biol Chem. 2006; 281(40):29431-5. DOI: 10.1074/jbc.C600167200. View

18.

Raol Y, Zhang G, Lund I, Porter B, Maronski M, Brooks-Kayal A . Increased GABA(A)-receptor alpha1-subunit expression in hippocampal dentate gyrus after early-life status epilepticus. Epilepsia. 2006; 47(10):1665-73. DOI: 10.1111/j.1528-1167.2006.00640.x. View

19.

Macdonald R, Olsen R . GABAA receptor channels. Annu Rev Neurosci. 1994; 17:569-602. DOI: 10.1146/annurev.ne.17.030194.003033. View

20.

Cendes F, Andermann F, Dubeau F, Gloor P, Evans A, Jones-Gotman M . Early childhood prolonged febrile convulsions, atrophy and sclerosis of mesial structures, and temporal lobe epilepsy: an MRI volumetric study. Neurology. 1993; 43(6):1083-7. DOI: 10.1212/wnl.43.6.1083. View