The dissertation is devoted to investigation of modulatory effects of main excitory neuromediator in CNS glutamate on inhibitory GABAergic transmission. Neuronal pairs in a dissociated hippocampal culture with at least one inhibitory monosynaptic connection were taken as a model system. The obtained kinetic, electric and pharmacological properties of inhibitory postsynaptic currents (IPSCs) indicate that in hippocampal culture IPSC is mediated by GABAA receptors. Present study demonstrated that glutamate (0.5-100 mM) brought about a depression of evoked IPSCs. The action of glutamate had two differet patterns of time-course. In about 60% of GABAergic synaptic pairs glutamate caused a compound depression with both fast and slow components. The rest of tested pairs exhibited only slow IPSP decrease. In the same time, in 60% of inhibitory pairs glutamate produced a shift of the apparent reversal potential of IPSCs into hyperpolarization, whereas no influence on Er(GABA) in other pairs was registered. Thi s discrimination is supposed to be associated with proximal or distal location of synaptic inputs for the postsynaptic neuron in given pair. In most cases, the depression taking place was long-lasting and irreversible contrary to no glutamate-induced LTD of EPSCs. The amount of inhibitory synaptic pairs, where long-term depression was observed, depended on duration of glutamate application. Glutamate influence on eIPSC amplitudes was non-desentitizing and non-saturating, i.e. the longer was application, the deeper depression in presence of glutamate has been achieved. As a possible consequence of non-saturation, concentration dependence of glutamate action was not fitted well with Hill equation. APV and CNQX decreased the percentage of glutamate-induced inhibition of eIPSCs, but had no effect on their recovery after glutamate had been taken off. Thus, the LTD is mediated mainly by metabotropic receptors (mGluRs) while STD by iGluRs. Although glutamate did not relyably change coeficient of variancies (CV) of evoked IPSC amplitudes, there was a clear increase in the paired-pulse ratio in 55% of tested pairs. Another evidence that presynaptic receptors are involved in glutamate-induced modulation of fast GABAergic synaptic transmission is both a decrease in frequency of miniature inhibitory postsynaptic currents and, in the presence of iGluR blockers, an increase in frequency of spontaneous activity. Two latter results indicate that activation of mGluRs, which are located on soma and dendrites, enhances excitability of interneurones while activation mGluRs, that are situated at inhibitory terminals, results in reduction of GABA release. Glutamate has also reduced mIPSC amplitudes and CV in the majority of cells (76%). Glutamate has also turned out to produce postsynaptic down-regulation of GABA transmission. That comes from its ability to diminish currents elicited by iontophoretic GABA application. This effect, most likely, is mediated by NMDA receptors. A suggestion was made that fast and short-time glutamate-in duced depression of GABAergic transmission arise mainly from activation of ionotropic glutamate receptors, which are located on postsynaptic membrane, while slow and long-time depression resultes from activation of presynaptic-terminal-located metabotropic ones. Being a certain way of excitotoxity, such a modulation of inhibition can occur in hippocampus in vivo under physiological and pathological conditions. However, a some possibility exists that such a pattern of modulation is typical for early stages of postnatal development when, in fact, fast GABAergic transmission may be excitory due to low intracellular concentration of Cl-. Thus, it seems quite possible that the pattern of glutamate-induced modulation of GABAergic synaptic transmission can change during the development of neronal network.
