2. Academic Validation
  3. NMDAR (2C) deletion in astrocytes relieved LPS-induced neuroinflammation and depression

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

  • Int Immunopharmacol. 2024 May 10:132:111964. doi: 10.1016/j.intimp.2024.111964.
Ruyan Gao 1,  Tahir Ali 2,  Zizhen Liu 3,  Axiang Li 4,  Kaiwu He 5,  Canyu Yang 6,  Jinxing Feng 7,  Shupeng Li 8
Affiliations

Affiliations

  • 1 State Key Laboratory of Chemical Oncogenomics, Guangdong Provincial Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, Guangdong, PR China, 518055. Electronic address: gaoruyan@pku.edu.cn.
  • 2 State Key Laboratory of Chemical Oncogenomics, Guangdong Provincial Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, Guangdong, PR China, 518055; Institute of Chemical Biology, Shenzhen Bay Laboratory Shenzhen 518132 China. Electronic address: tali@bs.qau.edu.pk.
  • 3 State Key Laboratory of Chemical Oncogenomics, Guangdong Provincial Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, Guangdong, PR China, 518055. Electronic address: ZzLiu@pku.edu.cn.
  • 4 Institute of Forensic Injury, Institute of Forensic Bio-Evidence, Western China Science and Technology Innovation Harbor, Xi'an Jiaotong University, Xi'an, People's Republic of China. Electronic address: liaxiang5045@stu.xjtu.edu.cn.
  • 5 State Key Laboratory of Chemical Oncogenomics, Guangdong Provincial Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, Guangdong, PR China, 518055. Electronic address: kaiwuhe@gmail.com.
  • 6 Institute of Forensic Injury, Institute of Forensic Bio-Evidence, Western China Science and Technology Innovation Harbor, Xi'an Jiaotong University, Xi'an, People's Republic of China. Electronic address: yangcanyu1996@stu.xjtu.edu.cn.
  • 7 Department of Neonatology, Shenzhen Children's Hospital, Shenzhen, China. Electronic address: szfjx2013@hotmail.com.
  • 8 State Key Laboratory of Chemical Oncogenomics, Guangdong Provincial Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, Guangdong, PR China, 518055; Institute of Chemical Biology, Shenzhen Bay Laboratory Shenzhen 518132 China; Department of Psychiatry, University of Toronto, Toronto, ON, Canada. Electronic address: lisp@pku.edu.cn.
PMID: 38603856 DOI: 10.1016/j.intimp.2024.111964
Abstract

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.

Keywords

Astrocytes; Depression; NMDARs; Neuroinflammation; PI3K Signaling.

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