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Accumulating evidence indicates that inherited astrocyte dysfunction can be a primary trigger for epilepsy development; however, the available data are rather limited. In addition, astrocytes are considered as a perspective target for the design of novel and improvement of the existing antiepileptic therapy. Piracetam and related nootropic drugs are widely used in the therapy of various epileptic disorders, but detailed mechanisms of racetams action and, in particular, their effects on glial functions are poorly understood. In this study, we explored the functional state of astrocytes in the dentate gyrus (DG) of Krushinsky-Molodkina (KM) rats genetically prone to audiogenic seizures and compared the action of piracetam on the DG astrocytes in KM and normal Wistar rats. Wistar and naïve KM rats which received injections of saline (control) or piracetam (100 mg/kg) for 21 days were recruited in our studies. Comparative analysis of control Wistar and KM rats revealed genetically determined abnormalities in DG astrocytes of KM rats including an increased expression of NFIA but a decreased GFAP, ALDH1L1, EAATs, and glutamine synthetase (GS). Piracetam treatment normalized the expression of all studied markers, except NFIA, in KM rats, while in Wistar rats, it potentiated only GS and NFIA. The results suggested that the nootropic and antiepileptic effects of piracetam may be, at least partially, mediated by the modulation of astroglia functions. In addition, analysis of NFIA and GS colocalization revealed the novel pattern of astrocyte heterogeneity in the DG which was significantly altered in epileptic rats but corrected by piracetam., (© 2024 Wiley Periodicals LLC.)