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  • The GABA A receptors containing the subunit are

    2021-09-14

    The GABA-A receptors containing the δ subunit are crucial for the mediation of non-synaptic inhibition in the dentate gyrus; thus, the decreased expression of the δ subunit may suggest a decrease in the inhibitory tone and an increase in the neuronal excitability. Moreover, the GABA-A receptors containing δ subunits are characterized not only by the extrasynaptic localization but also by the high affinity for GABA and a slow rate of desensitization [12]. The deficit in the GABA-A receptors containing δ subunits may cause a condition in which the physiological concentration of GABA is not sufficient to evoke the appropriate inhibitory response, consequently leading to the excessive neuronal activity observed in kindled animals. The reduction of the δ subunit expression in the dentate gyrus was also observed in other preclinical models of epilepsy, such as hippocampal electrical kindling, epilepsy following electrically induced status epilepticus, model of status epilepticus induced by kainic chem 8 synthesis injections and in pilocarpine-induced status epilepticus [13], [14]. Moreover, a direct association between an abundance of the α4 and δ subunits of GABAA receptors in the hippocampus and the seizures susceptibility has been proved in the mouse model of perimenstrual catamenial epilepsy [15]. It is important to note that we did not observe any changes in the δ subunits expression after a single subthreshold (30mg/kg) or convulsive (55mg/kg) dose of PTZ. This implies that changes in the δ subunit expression are a consequence of kindling development. Indeed, the results of other studies suggest that a decrease in the δ subunit mRNA level may be observed earlier, even 6h after status epilepticus induced by kainic acid injection, and is still observed after 30days [16]. The regulation of the tonic inhibition in the dentate gyrus is not only dependent on the δ subunit. It was demonstrated that the α4 subunit accompanies the δ subunit in the GABA-A receptors that mediate tonic inhibition [5]. Although a majority of α4 subunits co-express with δ subunits, some α4 subunits could be found in GABA-A receptors with a different subunit composition, e.g., with a γ2 subunit [4], [7]. The functional role of α4 subunits in the tonic inhibition seems to be important. In the knockout mice devoid of the α4 subunit, a deficiency of tonic chem 8 synthesis inhibition in the dentate granule cells and thalamic relay neurons was observed [3]. In our study, there were no significant changes in the expression of the α4 subunit in the fully kindled animals, but a tendency to increase its expression was observed. On the other hand, we found that a single injection of PTZ (at both doses of 30 and 55mg/kg) evoked a significant increase in the α4 subunit expression. This observation is in line with the results of other studies, which reported an increase in α4 mRNA levels in granule cells in the kainate model of epilepsy, in amygdala kindled rats and in animals in chronic phase after pilocarpine-induced status epilepticus [14], [16]. An increase in the expression of GABA-A receptors containing the α4 subunit, that possess a lower affinity for GABA, implies that maintaining tonic inhibition requires higher extracellular GABA concentration [3]. However, that adaptive mechanism is questionable, as in our previous study we demonstrated that in the PTZ-kindled rats, extracellular GABA level in the hippocampus was reduced compared to the control animals [17]. Regarding the mechanisms of kindling-induced changes in the GABA-A receptor subunits composition, several transcription factors are known to be activated by seizures, including brain derived neurotrophic factor (BDNF), cAMP response element binding protein (CREB), and early growth response factors (Egrs) [18]. It is suggested that these factors may regulate GABA-A receptor subunits genes expression. For example, it was demonstrated that BDNF activation of the TrkB receptor leads to induction of Egr3 synthesis. Egr3 binds to the Egr response element in the promotor region of the GABAARα4 subunit gene and increases in GABA-A α4 subunit expression [19].