GluR2 may drive neuroinflammation and cognitive impairments following peripherally repeated lipopolysaccharide exposures

Abstract Neuroinflammation has been demonstrated to play a key role in the pathogenesis of many neurological and neuropsychiatric diseases. Lipopolysaccharides (LPS), an element of the cell envelope of gram-negative bacteria, could activate the innate immune system to induce neuroinflammation and eventually lead to cognitive impairments. Accumulating evidence has suggested the presence of glutamate receptors (GluRs) on glial cells can induce glial activation. Therefore, we hypothesized that repeated lipopolysaccharide exposures could increase GluR levels and mediate microglia activation, eventually contributing to synaptic plasticity and cognitive impairments. In the present study, C57/BL6 mice were subjected to repeated LPS exposures to establish the animal model of neuroinflammation. The levels of GluRs, inflammatory cytokines, ionized calcium binding adaptor molecule 1 (Iba1), postsynaptic density protein 95 (PSD-95), synaptophysin 38 (SVP38), NMDA receptor 2A (GluN2A), and GluN2B were determined in the hippocampi. The dendritic spine density was evaluated in the CA1 of the hippocampi. Our results showed that repeated LPS exposures induced cognitive impairments, increased the levels of GluR1 and GluR2 and induced microglia activation, which were accompanied by significantly decreased GluN2B expression and dendritic spine density in the hippocampi. However, AMPAR antagonist CFM-2 administration reversed these abnormalities. In addition, microglia inhibitor minocycline also reversed these abnormalities, downregulated GluR2 but not GluR1 expresssion. In conclusion, our study demonstrated that GluR2 may be an important contributor to microglia mediated-neuroinflammation, leading to synaptic plasticity and cognitive impairments induced by repeated LPS exposures.