GABAA Receptor–Mediated IPSCs and α1 Subunit Expression Are Not Reduced in the Substantia Nigra Pars Reticulata of Gerbils With Inherited Epilepsy

Abstract

Domestic Mongolian gerbils, a model of inherited epilepsy, begin having spontaneous seizures at approximately 1.5 mo of age, making it possible to evaluate them during epileptic and pre-epileptic stages. Previous studies have shown that GABA binding is reduced in the substantia nigra pars reticulata (SNr) of both epileptic and pre-epileptic gerbils compared with controls, suggesting that reduced expression of GABAA receptors in SNr might be epileptogenic in this model. To test this hypothesis, we measured the expression of the GABAA receptor alpha1 subunit, the dominant alpha subunit expressed in the SNr, and evaluated GABAA receptor-mediated postsynaptic currents in SNr neurons. GABA(A) alpha1 subunit mRNA levels in substantia nigra-rich tissue from pre-epileptic animals were similar to controls, and immunocytochemistry for the alpha1 subunit showed similar strong expression in the SNr in both groups. Western analysis confirmed that expression of the alpha1 subunit protein was similar in substantia nigra-rich tissue from pre-epileptic and control gerbils. The frequency and amplitude of spontaneous inhibitory postsynaptic currents (IPSCs) and the frequency of miniature (m)IPSCs in SNr neurons of pre-epileptic gerbil were similar to those of controls. The amplitude of mIPSCs in the pre-epileptics was significantly larger than controls. Zolpidem, an alpha1 subunit-specific modulator of the GABAA receptor, was equally efficacious in prolonging the decay time of mIPSCs in both groups. Hence, contrary to the predictions of the hypothesis, mRNA and protein expression levels of the major GABAA receptor alpha subunit were normal, and neurons of the SNr in pre-epileptic gerbils displayed normal or enhanced IPSC frequencies and amplitudes. Therefore reduced expression of GABAA receptors in SNr is not likely to be an epileptogenic mechanism in this model.