NMDAR (2C) deletion in astrocytes relieved LPS-induced neuroinflammation and depression

• Published in: International immunopharmacology Vol. 132; p. 111964
• Main Authors: Gao, Ruyan, Ali, Tahir, Liu, Zizhen, Li, Axiang, He, Kaiwu, Yang, Canyu, Feng, Jinxing, Li, Shupeng
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 10.05.2024
• Subjects: Animals; Astrocytes; Astrocytes - drug effects; Astrocytes - metabolism; Depression; Depression - immunology; Hippocampus - metabolism; Hippocampus - pathology; Lipopolysaccharides; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neuroinflammation; Neuroinflammatory Diseases - drug therapy; Neuroinflammatory Diseases - immunology; NMDARs; Phosphatidylinositol 3-Kinases - metabolism; PI3K Signaling; Receptors, N-Methyl-D-Aspartate - genetics; Receptors, N-Methyl-D-Aspartate - metabolism; PI3K Signaling; Neuroinflammation; Depression; NMDARs; Astrocytes
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2024.111964

•Astyrocytic-NR2C KO (G-2C) mice possessed anti-depressant potential under LPS-induced stress conditions.•Astrocytic-NR2C deprivation prevented LPS-induced neuroinflammation.•Astrocytic-NR2C contributes to neuroinflammation-coinciding depression via PI3K/AKT signalling.•BPV(pic), a PTEN inhibitor treatment, attenuated the anti-inflammatory and anti-depressant potential of G-2C mice.•NF-kB and JNK antagonism reversed rescued BPV-induced changes. The link between neuroinflammation and depression is a subject of growing interest in neuroscience and psychiatry; meanwhile, the precise mechanisms are still being unrevealed. However, glial cell activation, together with cytokine level elevation, suggests a connection between neuroinflammation and the development or exacerbation of depression. Glial cells (astrocytes) communicate with neurons via their extracellular neurotransmitter receptors, including glutamate receptors NMDARs. However, these receptor roles are controversial and enigmatic in neurological disorders, including depression. Therefore, we hypothesized whether NMDAR subnit NR2C deletion in the astrocytes exhibited anti-depressive effects concurrent with neuroinflammation prevention. To assess, we prepared astrocytic-NR2C knockout mice (G-2C: GFAPCre+Grin2Cflox/flox), followed by LPS administration, behavior tests, and biochemical analysis. Stimulatingly, astrocytic-NR2C knockout mice (G-2C) did not display depressive-like behaviors, neuroinflammation, and synaptic deficits upon LPS treatment. PI3K was impaired upon LPS administration in control mice (Grin2Cflox/flox); however, they were intact in the hippocampus of LPS-treated G-2C mice. Further, PI3K activation (via PTEN inhibition by BPV) restored neuroinflammation and depressive-like behavior, accompanied by altered synaptic protein and spine numbers in G-2C mice in the presence of LPS. In addition, NF-κB and JNK inhibitor (BAY, SP600125) treatments reversed the effects of BPV. Moreover, these results were further validated with an NR2C antagonist DQP-1105. Collectively, these observations support the astrocytic-NR2C contribution to LPS-induced neuroinflammation, depression, and synaptic deficits.