Evidence for the interaction of COX-2 with mGluR5 in the regulation of EAAT1 and EAAT3 protein levels in the mouse hippocampus. The influence of oxidative stress mechanisms

Since we found that inhibition of cyclooxygenase-2 (COX-2) with concomitant application of a metabotropic glutamate receptor subtype 5 (mGluR5) antagonist (MTEP) down-regulates mGluR7 in the hippocampus (HC) and changes behavior of mice, our team decided to investigate the mechanism responsible for the observed changes. The amino acid glutamate (Glu) is a major excitatory neurotransmitter in the brain. Glu uptake is regulated by excitatory amino acid transporters (EAAT). There are five transporters with documented expression in neurons and glia in the central nervous system (CNS). EAATs, maintain the correct transmission of the Glu signal and prevent its toxic accumulation by removing Glu from the synapse. It has been documented that the toxic level of Glu is one of the main causes of mental and cognitive abnormalities. Given the above mechanisms involved in the functioning of the Glu synapse, we hypothesized modification of Glu uptake, involving EAATs as the cause of the observed changes. This study investigated the level of selected EAATs in the HC after chronic treatment with mGluR5 antagonist MTEP, NS398, and their combination using Western blot. Concomitant MTEP treatment with NS398 or a single administration of the above causes changes in LTP and modulation of EAAT levels in mouse HC. As EAATs are cellular markers of oxidative stress mechanisms, the E. coli lipopolysaccharide (LPS) challenge was performed. The modified Barnes maze test (MBM) revealed alterations in the mouse spatial learning abilities. This study reports an interaction between the mGluR5 and COX-2 in the HC, with EAAT1 and EAAT3 involvement.

Automated summary

The study investigated the impact of inhibiting cyclooxygenase-2 (COX-2) and applying a metabotropic glutamate receptor subtype 5 (mGluR5) antagonist (MTEP) on mGluR7 levels in the hippocampus (HC) and behavior of mice. It was found that modulation of glutamate (Glu) uptake through excitatory amino acid transporters (EAAT) plays a crucial role in maintaining Glu signal transmission and preventing toxic accumulation, which can lead to mental and cognitive abnormalities. Additionally, the study observed changes in long-term potentiation (LTP) and EAAT levels in the mouse HC after treatment with MTEP, NS398, and their combination, suggesting a complex interaction between mGluR5, COX-2, and EAATs.