Accelerated Establishment of Limbic Seizures in Aging Krushinsky-Molodkina Audiogenic Rats Is Associated With Neurodegeneration and Downregulation of the Glutamatergic Transmission in the Hippocampus.

Abstract

The prevalence of epileptic disorders is notably elevated in the elderly population. Meanwhile, epilepsy in aged patients is characterized by a distinct set of characteristics. However, the pecularities of molecular mechanisms underlying senile epileptogenesis still remain to be fully elucidated. The objective of the present study was to elucidate the specificity of seizure behavior and glutamatergic transmission in the hippocampus during the development of limbic/mesial temporal lobe epilepsy (TLE) in aging (18-month-old) Krushinsky-Molodkina (KM) audiogenic rats. To reproduce TLE conditions, animals were exposed to repetitive audiogenic seizure (AGS) stimulations, audiogenic kindling, for a period of 14 days. Behavioral analysis revealed that, similar to adult KM rats, audiogenic kindling in aging animals induced a progressive increase in the duration and severity of the limbic AGS phase, post-tonic clonus. However, in contrast to adults, in aging KM rats, the severity of the brainstem AGS component decreased during kindling, while limbic seizure progression was significantly faster, indicating faster epileptization of the limbic structures, including the hippocampus. Further, a comparison of aging KM rats, exposed to 14-day kindling, with non-stimulated (naïve) controls of the same age revealed seizure-induced loss of the hippocampal cells. These alterations were accompanied by a decrease in glutaminase, vesicular glutamate transporters, and AMPA receptor subunits, suggesting a downregulation of glutamate production and glutamatergic transmission. The obtained results collectively indicate that the process of aging in KM rats is associated with accelerated TLE establishment, which is accompanied by significant alterations in the key components of the glutamatergic system in the hippocampus.