期刊
JOURNAL OF NEUROSCIENCE
卷 26, 期 44, 页码 11342-11346出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.3329-06.2006
关键词
spontaneous seizures; epilepsy; gene therapy; rat; AAV; GABA
资金
- NICHD NIH HHS [P30 HD23979, P30 HD026979] Funding Source: Medline
- NIDDK NIH HHS [DK63973, DK47757, R01 DK063973, P30 DK047757] Funding Source: Medline
- NINDS NIH HHS [R01 NS038595, F31 NS051943, NS050393, NS38690, NS51943, R01 NS050393, R01 NS038690, R01 NS051710, NS38595, NS051710] Funding Source: Medline
Differential expression of GABAA 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 alpha 1 subunits and increased expression of alpha 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 alpha 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 alpha 1 subunit mRNA and protein in DG at 1-2 weeks after SE. Enhanced alpha 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 alpha 1 subunit levels are important determinants of inhibitory function in hippocampus.
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