Expression of GABA-A Receptors and Cation-Chloride Cotransporters in the Hippocampus of Krushinsky–Molodkina Audiogenic Rats during the Postnatal Development

Abstract

Epilepsy development can be caused by impaired postsynaptic action of GABA that is mediated by altered expression of GABA-A receptors and cation-chloride cotransporters, KCC2 (K⁺/Cl^– cotransporter 2) and NKCC1 (Na⁺/K⁺/Cl^– cotransporter 1). In the present study, we analyzed the expression of GABA-A receptors, KCC2, and NKCC1 in the hippocampus of Krushinsky–Molodkina (KM) rats, genetically prone to audiogenic seizures (AGS), during the first few months of the postnatal development (at P15, P60, and P120). Wistar rats of the corresponding ages were used as the control groups. In the hippocampus of KM pups, we observed downregulation of both KCC2 and NKCC1; however, the expression of GABA-A receptor α1-subunit (GABAAR(α1)) was increased. Moreover, KCC2 was not detected in an abnormally broad region of the granular layer, indicating the Cl^– imbalance and impaired GABA-mediated inhibition in postsynaptic targets of GABA. These results suggested a delayed maturation of the hippocampal GABAergic system in KM rats in comparison with Wistar rats. In adult KM rats (P120) with fully developed susceptibility to AGS, normalization of both KCC2 and NKCC1 expression and KCC2 phosphorylation in the hippocampus was revealed. In contrast, GABAAR(α1) expression was decreased. We supposed that lower expression of GABA-A receptors in the hippocampus of adult KM rats might contribute either to the establishment of increased convulsive readiness or to hyperexcitation of the hippocampus during audiogenic kindling.