Enhancing GABA_AReceptor α1 Subunit Levels in Hippocampal Dentate Gyrus Inhibits Epilepsy Development in an Animal Model of Temporal Lobe Epilepsy

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 ␣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.

Effect of the α subunit subtype on the macroscopic kinetic properties of recombinant GABAA receptors

“…This pattern is observed in models of hyperexcitability, in which faster IPSC decay rates are associated with an increased seizure susceptibility (Smith et al, 1998). The increase in seizure activity could be reduced by decreasing α4 subunit expression (Smith et al, 1998) or by increasing α1 subunit expression (Raol et al, 2006). Our results suggest that either of these changes in subunit expression would slow the deactivation rate.…”

Silk polymer-based adenosine release: Therapeutic potential for epilepsy

“…These range from electrical and magnetic stimulation [36][37][38][39], focal cooling [40], cell therapies [6,7,13,41,42], and gene therapies [43][44][45][46], to the ketogenic diet [47,48]. We recently established a neurochemical rationale for focal adenosine augmentation therapies (AATs).…”

Expression of GABAA receptor α1 subunit mRNA and protein in rat neocortex following photothrombotic infarction

“…The α 1 subunit is abundant in the rat cerebral cortex (Wisden et al, 1992;Paysan et al, 1994), shows a distinct pattern of distribution throughout the adult brain (Pirker et al, 2000), is sensitive to benzodiazepine modulation, and mediates sedative and anticonvulsant activity (Fisher et al, 1997;Hevers and Luddens, 1998;Crestani et al, 2002;Kralic et al, 2002;Mohler, 2007). Alterations in or abnormalities of α 1 subunit expression may lead to the development of neurological and behavioral disorders (Fisher, 2004;Mohler, 2006); however, the overall importance of α 1 subunit changes for the development of epilepsy is not fully determined (Fritschy et al, 1999;Kumar et al, 2006;Loup et al, 2006;Raol et al, 2006a).…”