Romanov A. The role of acid-sensitive ion channels in the rat hippocampus neural networks’ activity modulation under normal conditions and in pathological synchronization

The dissertation is devoted to the study of the role of acid-sensitive ion channels (ASIC) in the modulation of rat hippocampal neural networks in physiological conditions and while generating the epileptiform activity. We studied for the first time the effect of ASIC channel blocking in epileptic models of the hippocampus using the latest selective ASIC1a channel blocker 5b. We determine the optimal conditions for perfusion and the carbogenization of the brain slices, which is critical for reliable research. Here we show that perfusion rate and the level of slices' oxygenation modifies the power of the induced epileptiform activity. For the first time, we show functional differences in the development of epileptiform activity in the ventral and dorsal parts of the hippocampus. We stadied that ASIC1a blockade using low-magnesium and 4-ap models of epileptiform activity induction leads to a decrease in the frequency characteristics of epileptiform activity and reduces the frequency of spontaneous generation of action potentials in the hippocampus. Possible mechanisms that mediate the above changes also have been investigated. It was first demonstrated that the removal of ASIC channels from the synaptic conduction cascade does not affect the excitatory synaptic activity, while significantly increasing the frequency characteristics of inhibitory activity, thus shifting the balance between inhibition and excitation due to ASIC1a blockade leads to a decrease in total excitation and leads to antiepileptic effect. Summarizing the results, we can say that this work confirms the idea of the presynaptic effect of ASIC channels on the probability of activation of GABA receptors, given that the blockade of ASIC1a does not affect the amplitude characteristics of excitatory postsynaptic currents. Using the latest selective ASIC1a blocker, we demonstrate the role of these channels in the regulation of inhibitory synaptic activity in the central nervous system and their importance as targets for future antiepileptic drugs.