Enhancing GABA(A) receptor alpha 1 subunit levels in hippocampal dentate gyrus inhibits epilepsy development in an animal model of temporal lobe epilepsy.
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.
Raol
YogendraSinh H
YH
Division of Neurology, Pediatric Regional Epilepsy Program, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
Lund
Ingrid V
IV
Bandyopadhyay
Sabita
S
Zhang
Guojun
G
Roberts
Daniel S
DS
Wolfe
John H
JH
Russek
Shelley J
SJ
Brooks-Kayal
Amy R
AR
D000818:Animals; D004195:Disease Models, Animal; D004833:Epilepsy, Temporal Lobe / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control*; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D008297:Male; D009433:Neural Inhibition / Q000502:physiology; D020534:Parahippocampal Gyrus / Q000378:metabolism*; D021122:Protein Subunits / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*
C546240:GABRA1 protein, human; C546242:Gabra1 protein, rat; D021122:Protein Subunits; D011963:Receptors, GABA-A