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  • br Methods br Results br Discussion Significant alterations

    2022-01-05


    Methods
    Results
    Discussion Significant alterations in the expression of genes related to the glutamatergic system have been shown in several experimental models of epilepsy; however, in most studies focused on acute changes or modifications in expression, these were investigated during the chronic phase. In the present study, we analyzed the changes in gene expression CARIPORIDE during the latent period of a rat lithium-pilocarpine model. Epileptogenesis is believed to occur during this phase [7]. We revealed changes in gene expression in various structures of the temporal lobe and the prefrontal cortex. Because the functions of the ventral and dorsal hippocampus differ significantly [30], analyses of gene expression were carried out separately for these regions. This allowed us to identify region-specific changes in expression during epileptogenesis. We found that EAAT1 expression was not altered in any of the examined CARIPORIDE areas, while we revealed an increase in the mRNA level of glial glutamate transporter EAAT2 in the medial prefrontal cortex and dorsal hippocampus and a decrease in the mRNA level of neuronal transporter EAAT3 in the entorhinal cortex. The increase in the production of EAAT2 mRNA can be considered a compensatory reaction given that an increase in excitation occurs after the administration of pilocarpine. The increased production of EAAT2 may also have neuroprotective and antiepileptogenic effects. Indeed, EAAT2 transgenic mice, which have a 1.5–2 fold increase in EAAT2 protein levels as compared to their non-transgenic counterparts, exhibit smaller post-SE mortality rate and chronic seizure frequency in a lithium-pilocarpine model [31]. An activator of glutamate transporter EAAT2, LDN/OSU-0212320, substantially reduced mortality, neuronal death, and spontaneous recurrent seizures in a murine pilocarpine-induced temporal lobe epilepsy model [32]. Published data on the expression of EAATs after seizures are contradictory. The significantly increased protein level of EAAT1 expression was detected 3 h and 1 d after pentylenetetrazole-induced seizures, suggesting neuroprotective effect [33]. A significant initial increase in dorsal hippocampal EAAT2 immunoreactivity was observed 1 day after kainite-induced SE, followed by a marked down-regulation at 4 and 7 days after SE, with a return to near control levels by 30 days after SE [34]. In contrast, the down-regulation of the mRNA expression and protein levels of EAAT1 and EAAT2 in the cortical areas was reported during the latent period of the lithium-pilocarpine model [35]. These results suggest that the changes in production of EAATs after seizures can prevent or enhance epileptogenesis depending on the experimental models. A week after the seizures, alterations in the gene expressions of the AMPA receptor subunits were found only in the ventral hippocampus and temporal cortex. We identified the down-regulation of GluA1 gene expression in the ventral hippocampus, which corresponds to the results of previous studies [12,13]. We also found a decrease in the expression of the GluA2 gene in the temporal cortex. The AMPA receptors containing GluA2 subunits are calcium-impermeable [16]. A decrease in the number of GluA2-containing receptors can lead to an increase in the glutamate-mediated penetration of Ca2+ into the cell and excitotoxicity [36]. Consequently, a decrease in the expression of the GluA2 subunit may be one of the factors that induces neurodegenerative changes in the lithium-pilocarpine model. We detected a decrease in the production of GluN1 mRNA in the temporal and entorhinal cortexes of rats following the seizures. Because the GluN1 subunit is obligatory for NMDA receptors, this result indicates a potential reduction in the number of NMDA receptors in these cortical areas. A down-regulation of the mRNA expression of the GluN1 subunit in the cerebral cortex, but not in the hippocampus, was also observed by Lopes et al. during the latent period (5 days after SE) [35]. These changes are most likely time- and structure-dependent because other studies have revealed an increase in GluN1 expression in the hippocampus 24 h after pilocarpine injections [37].