Alterations of GABAergic transmission in the hippocampus of aging Krushinsky-Molodkina rats genetically prone to audiogenic seizures

Abstract

Aging is accompanied with attenuation of the inhibitory γ-aminobutyric acid (GABA) neurotransmission, while age-related neurological disorders including neurodegenerative diseases and epilepsy can exacerbate this deficit. However, the interrelation between age-dependent dysfunction of GABAergic transmission and inherited epileptic predisposition remains unclear. In this study, we analyzed the markers of GABAergic system in the hippocampus of aging (18-month-old) Krushinsky-Molodkina (KM) rats genetically prone to audiogenic seizures (AGS). To delineate the inherited background, we compared naïve KM rats with no AGS experience with Wistar rats of the corresponding age. The results showed that GABA-positive cell numbers and glutamate decarboxylase 67 (GAD67) expression in the hippocampus of aging KM rats were increased indicating the higher activity of GABAergic interneurons and GABA production. Increased colocalization of Fos-related antigen 1 and GAD67, along with elevated parvalbumin, additionally confirmed this suggestion. At the same time, unchanged expression of vesicular GABA transporter, synaptic vesicle glycoprotein 2A, and synaptosomal-associated protein, 25 kD, together with unaltered GABA content in fibers and terminals, suggested that the activity of GABA exocytosis corresponded to the age-related norm. Analysis of proteins, regulating postsynaptic GABA action, revealed normal expression of cation-chloride transporters, however, GABA-A receptors were significantly decreased. Thus, we suppose that the increased activity of the inhibitory GABAergic interneurons of aging KM rats may restrict hyperexcitability of the hippocampus, in particular, during single AGS. However, GABA receptor deficit may, in opposite, contribute to overexcitation of the hippocampus during repetitive seizures and promote excitotoxic damage of the hippocampal cells at the advanced age.

Keywords: Aging; Audiogenic epilepsy; Hippocampus; Krushinsky-Molodkina rats; γ-aminobutiric acid.