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  • In our study the changes in

    2021-09-14

    In our study, the changes in the α4 and δ subunit expression were accompanied by a significant increase in γ2 subunit expression in almost all analysed hippocampal structures in the fully kindled animals. In contrast, an acute injection of PTZ at a convulsive dose (55mg/kg) evoked a potent decrease in the γ2 subunit expression. The γ2 subunits are typical of synaptically located GABA-A receptors that mediate phasic inhibition [3]. In previous studies, it has been shown that epileptic seizures evoked by kainic BRL 37344, sodium salt injection may cause rapid internalization of GABA-A receptors containing γ2 subunits in hippocampal structures [20]. In the latent phase (30days after kainic acid administration), a subsequent increase in γ2 subunit expression was observed [20]. Similarly, an increased γ2 subunits labelling was noticed during the chronic phase after pilocarpine-induced status epilepticus [14]. Rapid internalization of the GABA-A receptors containing γ2 subunits is not the only reaction to the excessive neuronal activity. In the model of kainic acid-induced status epilepticus, an initial (24h) pronounced decrease in the expression of γ2 subunit mRNA was demonstrated, followed by a potent increase in its expression 30 and 90days after kainic acid injection [13]. In that context, a rapid decrease in γ2 subunit expression in response to seizures seems to be a resultant of a fast internalization of GABA receptors and a transient decrease in its transcription. The observed increase in γ2 subunit expression in the fully kindled animals may be an adaptive reaction to decreased tonic inhibition, which is a consequence of a decrease in δ subunit expression. It is possible that overexpressed γ2 subunits replace the function of δ subunits in the extra- and peri-synaptically located GABA-A receptors. On the other hand, the substitution of δ by the γ2 subunit may not be fully effective because the activation of GABA-A receptors containing a γ2 subunit needs a much higher GABA level [3]. In our study, we also assessed the expression of α1 subunit, which is the most abundant type of GABA-A receptor α subunits [3]. We observed a potent increase in the expression of α1 subunit in all analysed hippocampal structures in the fully kindled animals. The expression of α1 was also increased after an acute convulsive dose of PTZ (55mg/kg) but was restricted to the dentate gyrus only. A similar effect was observed in rats after pilocarpine-induced status epilepticus; however, an increase in α1 subunit expression was limited to the dentate gyrus [21]. Similarly, a long-lasting increase (after 30 and 90days) in the level of α1 subunit mRNA was observed after kainic acid-induced seizures [13]. In the context of our results and data obtained by other authors, an increase in α1 subunit expression may represent an adaptive mechanism to an excessive neuronal activity. On the other hand, in clinical studies, in resected brain tissue from patients with refractory epilepsy a significant decrease of α1 subunit expression was observed [22]. A reason for these discrepancies is not known, but may be related to the fact that resected tissue from the epileptic focus is characterized by degenerative lesions. However, in our model, we did not observe any significant degenerative changes in the hippocampus (Fig. 7). In our study, we did not observe pronounced changes in the expression of GABA transporters in response to PTZ kindling and the acute PTZ injection either. The only significant increase in the expression of neuronal GABA transporter was observed in the CA1 region in the fully kindled animals (by 25%). Increased expression of GAT-1, which is predominantly responsible for the uptake of GABA after synaptic release (approximately 85% of released GABA is taken up by GAT-1), may diminish the GABA level and reduce the amount of GABA that reaches peri- and extra-synaptic GABA-A receptors [23]. That sequence of events may consequently lead to a deficit in GABA inhibition. Nevertheless, the pattern of changes in the expression of GATs in epilepsy models is not unequivocally demonstrated. It can be assumed that changes in the expression of GATs are strongly related to the particular epilepsy model. In the hippocampus of seizure-sensitive gerbils (SSG), the density of GAT-1 immunoreactivity decreased 0.5h after seizures but returned to basal values after 12h. At the same time, no changes in GAT-3 expression were observed [24]. In contrast, other authors demonstrated a significant increase in the hippocampal GAT-1 mRNA expression in amygdala kindled rats at 1 and 4h after last kindled seizures [25]. All changes in mRNA expression returned to basal levels by 24h after the last kindled seizures, indicating that the increases in GABA transporter mRNA seem to be a transient response to seizure activity. In turn, in patients with drug-resistant TLE and hippocampal sclerosis, lower levels of GAT-1 and GAT-3 were observed in the hippocampal structures, most probably due to generally occurring degenerative changes [26]. Nevertheless, the role of GATs in the regulation of neuronal activity should not be underestimated. In the mice lacking GAT-1, a potent increase in GABAergic inhibition was noticed [27]. Furthermore, one of the GAT-1 antagonists − tiagabine is used clinically as an antiepileptic drug.