Abstracts

The substantia nigra pars reticulata (SNR) plays an important role in seizure control. There has been evidence that impairment of tonic GABA current may contribute to the development of generalized epilepsy in humans. We have found that the delta subunit, an important component of extrasynaptic GABAA receptors mediating tonic current, is present in the SNR and its expression significantly decreases with age in male and female rats. Thus, the objective of the current study was to determine whether tonic GABA current is present in GABAergic neurons and whether its magnitude changes with age. Furthermore, we studied alterations in phasic GABA inhibition as a function of age and sex., We studied two groups of Sprague-Dawley male and female rats at postnatal days (P) 10-15 and older than P22. Whole-cell patch clamp recordings were made from electrophysiologically identified nigral GABAergic cells in the presence of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and tetrodotoxin (TTX). Gabazine 500 nM was applied to inhibit GABAA receptor-mediated postsynaptic currents (mIPSCs). GABAA tonic current was revealed by bath-applied bicuculline 100 uM and was measured as the change in baseline current before and after bicuculline. IPSCs were analyzed before TTX and gabazine were applied., The tonic GABA current was present in GABAergic neurons in younger rats, however it was significantly lower in older animals. On the contrary, frequency and amplitude of phasic GABA inhibition was higher after P22 compared with younger rats. We did not find significant differences between sexes in either parameter., The tonic GABA current can be revealed in GABAergic SNR neurons. Although there is no apparent difference between males and females, the magnitude of tonic GABA inhibition significantly decreases with age. These findings can be explained by the age-related decrease in delta subunit expression in SNR neurons and the absence of sex differences in its expression. On the other hand, phasic GABA inhibition prevails later in development probably reflecting more dense synaptic connections onto GABAergic neurons or increased expression of synaptic GABAA receptors. Given the importance of SNR GABAergic neurons in seizure control, these findings could facilitate treatment of epilepsy based on the maturational state of the brain., (Supported by NS 20253, NS045243 from NINDS and an RSRF grant.)