Comparative Investigation of Expression of Glutamatergic and GABAergic Genes in the Rat Hippocampus after Focal Brain Ischemia and Central LPS Administration

Abstract

Among the responses in the early stages of stroke, activation of neurodegenerative and proinflammatory processes in the hippocampus is of key importance for the development of negative post-ischemic functional consequences. However, it remains unclear, what genes are involved in these processes. The aim of this work was a comparative study of the expression of genes encoding glutamate and GABA transporters and receptors, as well as inflammation markers in the hippocampus one day after two types of middle cerebral artery occlusion (according to Koizumi et al. method, MCAO-MK, and Longa et al. method, MCAO-ML), and direct pro-inflammatory activation by central administration of bacterial lipopolysaccharide (LPS). Differences and similarities in the effects of these challenges on gene expression were observed. Expression of a larger number of genes associated with activation of apoptosis and neuroinflammation, glutamate reception, and markers of the GABAergic system changed after the MCAO-ML and LPS administration than after the MCAO-MK. Compared with the MCAO-ML, the MCAO-MK and LPS challenges caused changes in the expression of more genes involved in glutamate transport. The most pronounced difference between the responses to different challenges was the changes in expression of calmodulin and calmodulin-dependent kinases genes observed after MCAO, especially MCAO-ML, but not after LPS. The revealed specific features of the hippocampal gene responses to the two types of ischemia and a pro-inflammatory stimulus could contribute to further understanding of the molecular mechanisms underlying diversity of the post-stroke consequences both in the model studies and in the clinic.

Genes Involved by Dexamethasone in Prevention of Long-Term Memory Impairment Caused by Lipopolysaccharide-Induced Neuroinflammation

“…Excitotoxicity associated with glutamate accumulation in the extracellular space is regarded among the reasons for memory impairment. The increased expression of the Slc1a2 gene encoding transporter for glutamate reuptake from the synaptic cleft was previously observed in the hippocampus one day after the single central administration of LPS [49], but not at 3 months in the present study. At the same time, in LPS-exposed rats pretreated with DEX, the expression in Slc1a2 significantly increased 3 months after the drug administration, indicating enhanced glutamate clearance in DEX-pretreated animals.…”

“…The activating effects of glutamate, the main excitatory neurotransmitter in the mammalian brain, on post-synaptic neurons occur via ionotropic and metabotropic receptors and often include Ca 2+ influx [47]. The functional properties of the Ionotropic receptors were determined by the composition of the subunits, each of which was encoded by a separate gene [48,49]. GRIN2A (Glutamate Ionotropic Receptor NMDA Type Subunit 2A)containing hippocampal NMDARs (N-methyl-d-aspartate receptors) were shown to play an important role in synaptic plasticity, learning and memory [50].…”