Aging of Krushinsky-Molodkina audiogenic rats is accompanied with pronounced neurodegeneration and dysfunction of the glutamatergic system in the hippocampus

Abstract

Advancing age strongly correlates with an increased risk of epilepsy development. On the other hand, epilepsy may exacerbate the negative effects of aging making it pathological. In turn, the possible link between aging and epileptogenesis is dysregulation of glutamatergic transmission. In the present study, we analyzed the functional state of the glutamatergic system in the hippocampus of aging (18-month-old) Krushinsky-Molodkina (KM) audiogenic rats to disclose alterations associated with aging on the background of inherited predisposition to audiogenic seizures (AGS). Naïve KM rats with no AGS experience were recruited in the experiments. Wistar rats of the corresponding age were used as a control. First of all, aging KM rats demonstrated a significant decrease in cell population and synaptopodin expression in the hippocampus indicating enhanced loss of cells and synapses. Meanwhile, elevated phosphorylation of ERK1/2 and CREB and increased glutamate in the neuronal perikarya were revealed indicating increased activity of the rest hippocampal cells and increased glutamate production. However, glutamate in the fibers and synapses was mainly unchanged, and the proteins regulating glutamate exocytosis showed variable changes which could compensate each other and maintain glutamate release at the unchanged level. In addition, we revealed downregulation of NMDA-receptor subunit GluN2B and upregulation of AMPA-receptor GluA2 subunit, which could also prevent overexcitation and support cell survival in the hippocampus of aging KM rats. Nevertheless, abnormally high glutamate production, observed in aging KM rats, may provide the basis for hyperexcitability of the hippocampus and increased seizure susceptibility in old age.