Long-Term Audiogenic Kindling Induces Pronounced Downregulation of the GABAergic System in the Hippocampus of Krushinsky–Molodkina Rats

Abstract

Downregulation of inhibitory GABAergic transmission is closely connected with the development and progression of epilepsy; however, further studies are still needed to provide the complex and detailed picture of corresponding pathological alterations and their contribution to epileptogenesis. In the present study, we performed the comprehensive analysis of GABAergic system in the hippocampus of Krushinsky–Molodkina (KM) audiogenic rats, exposed to prolonged audiogenic kindling to reproduce the condition of temporal lobe epilepsy (TLE). According to the kindling protocol, KM rats were exposed to 21 daily seizure stimulations, whereas unstimulated (naive) KM rats were used as a control. Obtained results showed that 21-day kindling was associated with a pronounced decrease in the expression of glutamate decarboxylase 67 (GAD67) and co-localization of GAD67 with active cAMP-response element-binding protein (CREB), indicating reduced activity of GABAergic interneurons and GABA production. In addition, we observed decreased expression of synaptic vesicle glycoprotein 2A (SV2A) and lower co-localization of vesicular GABA transporter (VGAT) with active phosphorylated synapsin I, suggesting an impaired presynaptic GABAergic vesicle function. Moreover, dysregulation of GABA-A receptor and cation-chloride transporter expression was detected, which could also exacerbate the dysfunction of GABAergic system in the hippocampus. Thus, the results suggest that prolonged audiogenic kindling in KM rats, resulting in the stabilization of severe limbic seizures and increased mortality, is associated with a pronounced and multifaceted dysregulation of GABAergic transmission in the hippocampus.