Abstracts

We have previously shown that in the substantia nigra reticulata (SNR) of both male and female neonatal rats, GABA(A) receptor activation causes neuronal depolarization. The switch of GABA(A) receptors from depolarizing to hyperpolarizing occurs earlier in female SNR neurons (around postnatal days 10-12 (PN10-12)) compared to male (still depolarizing at PN17). Three episodes of kainate (KA) - induced status epilepticus (SE) at PN4, PN5, and PN6 accelerate the switch of GABA(A) receptors from depolarizing to hyperpolarizing in the rat SNR of both sexes. It is also known that one of the factors that regulate the functional maturation of GABA(A) receptors is the level of expression of the neuronal-specific potassium chloride cotransporter KCC2. We tested therefore the effect of KA-induced SE at PN4-6 on the level of KCC2 mRNA expression in the SNR of PN10 male and female rats. Sprague-Dawley male and female rats were subjected to 3 episodes of KA-induced status epilepticus (SE) at PN4 (KA 1.5 mg/kg intraperitoneally (ip)), PN5 (KA 2 mg/kg ip) and PN6 (KA 2.5 mg/kg ip). Controls received saline injections and were kept separated from their dams for the same period as the pups subjected to SE (6-7 hours). Rats were sacrificed at PN10 and brains were processed with a KCC2-specific in situ hybridization. KCC2 cellular mRNA expression was compared semi-quantitatively with signal densitometry. Saline-injected female PN10 pups had increased levels of KCC2 mRNA in the SNR compared with saline-injected male PN10 pups. In both sexes, KA-induced SE (PN4-6) further increased KCC2 mRNA expression in PN10 SNR neurons, compared to same-sex rats. (1) KCC2 mRNA expression in female PN10 rat SNR is higher than in male and correlates therefore with the earlier time of switch of GABA(A) receptors to hyperpolarizing in female SNR neurons. (2) KA-induced seizures in early postnatal life increase KCC2 mRNA expression in the SNR in both sexes. These changes in KCC2 expression may explain the acceleration in the functional maturation of the GABA(A) receptors in the SNR of rats that experienced early life seizures. By altering KCC2 expression and the function of GABA(A) receptors, early life SE may therefore alter the phenotype and function of the SNR in seizure control. (Supported by NIH NINDS NS 45243 and NS 20253 grants.)