Comparative analysis of the nigrostriatal system in Wistar rats and rats prone to seizures

Abstract—Functional activities of dopaminergic, GABAergic and glutamatergic neurons were studied in the nigrostriatal system of Krushinsky–Molodkina (KM) rats genetically prone to audiogenic seizures as compared with control Wistar rats. In KM rats, a reduced activity of GABA-and dopaminergic neurons was detected in the substania nigra, while glutamatergic transmission remained intact. In the striatum of both KM and Wistar rats, no significant differences were found in levels of the GABA-synthesizing enzymes, GAD65/67 and phospho-tyrosine hydroxylase, however, an increased level of D1 dopamine receptor and decreased of D2 dopamine receptor imply possible upregulation of glutamatergic neurotransmission. Indeed, an increased expression of vesicular glutamate transporter VGlut2 and the NMDA receptor NR2B subunit was revealed in the striatum of KM rats. While the striatum glutamatergic fibers were demonstrated to express phosphorylated ERK1/2 kinases, both the striatum and substantia nigra in KM rats exhibit an increased activity of ERK1/2. This correlates with intense exocytosis, as evidenced by a decreased level of SNAP25 protein. Activation of the glutamatergic system may result, among other reasons, from the disruption of the inhibitory effect of the substantia nigra dopamine- and GABAergic systems innervating the striatum. We suggest that the increased activity of the striatum glutamatergic neurons in KM rats lacking adequate dopamine- and GABAergic inhibitory feedback may, at least in part, account for heightened convulsive readiness in KM rats.