The current study demonstrates that rats experiencing pilocarpine-induced SE at P10 respond differently than those subjected to SE in adulthood (). Unlike rats experiencing SE as adults, P10-SE rats do not become epileptic and the alterations in hippocampal GABARs in P10-SE rats are of lesser magnitude and in the opposite direction from those seen in adult SE rats. DGNs from P10-SE rats show increased expression of GABAR α1 subunit mRNA and enhanced zolpidem augmentation of GABA-mediated currents compared with controls. In contrast, GABAR α1 subunit expression in DGNs is decreased after SE in adulthood and zolpidem potentiation of GABA-mediated currents is reduced (Brooks-Kayal et al., 1998
). Further, the α4, β3 and δ subunits are all up-regulated and the β1 subunit is down-regulated in adult SE rats, while none of these subunits are changed following P10 SE. Taken together these findings demonstrate that the effects of SE on GABARs are highly age-dependent and suggest that the immature dentate may have a selective resistance to GABAR changes after SE compared with the adult.
Consequences of pilocarpine-induced SE
Rats do not develop epilepsy after pilocarpine-induced SE at P10 () in contrast to the nearly uniform development of spontaneous recurrent seizures in rats experiencing SE as adults (Gibbs et al., 1997
; Brooks-Kayal et al., 1998
; Shumate et al., 1998
). This relative protection from development of epilepsy after P10 SE could be related, in part, to the increased GABAR α1 subunit expression. Dentate gyrus serves as a gate in the hippocampal circuit (Heinemann et al., 1992
), and the increased GABAR expression in DGN following P10 SE could augment dentate gyrus inhibition and prevent excessive excitation from propagating into hippocampus. In addition, the up-regulation of α4 and δ subunits and the associated increase in zinc inhibition of GABA-currents that are hypothesized to result in a “failure of inhibition” in dentate after adult SE (Buhl et al., 1996
; Brooks-Kayal et al., 1998
) did not occur after P10 SE. Thus, it is possible that age-dependent differences in SE-induced GABAR effects could contribute to the selective resistance of the immature brain to epileptogenesis. As both anatomical and molecular consequences of SE vary based on the age at which it occurs (), however, further studies will be needed to determine whether differential effects on GABAR properties contribute to this difference in the rate of later epilepsy development.
The mechanisms regulating GABAR expression are not well understood. GABAR α1 subunit expression in DGNs increases markedly during the first postnatal month (Laurie et al., 1992
; Brooks-Kayal et al., 2001
). Several lines of evidence suggest that neuronal activity (Meinecke and Rakic, 1990
; Huntsman et al., 1994
; Holopainen and Lauren, 2003
), specifically synaptic signaling through the NMDA selective glutamate receptor (Memo et al., 1991
; Harris et al., 1995
; Zhu et al., 1995
) may be critical for stimulating GABAR α1 receptor subunit expression. Thus the increased α1 subunit expression after P10 SE could be an “over-maturation” of DGN GABARs due to the excessive neuronal activity associated with SE. On the contrary, the diminished α1 expression after SE in adulthood suggests a regression of mature DGN to a more immature state. Determining whether this difference is due to a derangement of “normal” developmental cues for GABAR expression or due to signaling mechanisms that are unique to SE will require additional investigation. These findings reinforce the need for better understanding of age-related differences in the consequences of SE and the mechanisms underlying these differences in order to develop optimal therapeutic approaches for the treatment of epilepsy throughout the lifespan.