2. Academic Validation
  3. NR2B-CaMKII signaling in the dentate gyrus driven by astrocytic P2Y1Rs mediates the antidepressant effect of low-dose LPS

NR2B-CaMKII signaling in the dentate gyrus driven by astrocytic P2Y1Rs mediates the antidepressant effect of low-dose LPS

  • Brain Behav Immun. 2026 Jul:135:106529. doi: 10.1016/j.bbi.2026.106529.
Minxiu Ye 1,  Chao Huang 2,  Yiming Gu 2,  Xu Lu 2,  Tao Zhu 3,  Yi Zhang 4
Affiliations

Affiliations

  • 1 Department of Pharmacy, Kunshan Hospital of Traditional Chinese Medicine, #388 Zuchongzhi South Road, Kunshan, Suzhou 215300, Jiangsu, China.
  • 2 Department of Pharmacology, School of Pharmacy, Nantong University, #9 Seyuan Road, Nantong 226019 Jiangsu, China.
  • 3 Department of Pharmacy, Affiliated Hospital of Nantong University, #20 Xisi Road, Nantong 226001 Jiangsu, China.
  • 4 Department of Pharmacy, Yancheng No. 1 People's Hospital, Affiliated Hospital of Medical School, Nanjing University, #66 Renmin South Road, Yancheng 224006, Jiangsu, China. Electronic address: [email protected].
PMID: 41796645 DOI: 10.1016/j.bbi.2026.106529
Abstract

Microglial decline in the dentate gyrus is an important mechanism in the development of depression-like behaviors in stressed Animals. Reversing this decline with low-dose lipopolysaccharide (LPS) can produce rapid antidepressant effects, yet the underlying mechanisms remain incompletely understood. Our previous work identified a critical role for astrocytic P2Y1 Receptor (P2Y1R) activation and subsequent dentate gyrus extracellular signal-regulated kinase 1/2 (ERK1/2)-brain-derived neurotrophic factor (BDNF) signaling in the antidepressant effect of low-dose LPS. This study elucidates the signaling cascade linking astrocytic P2Y1R mobilization to the antidepressant effect of low-dose LPS. We found that low-dose LPS promoted glutamate release through ATP-triggered astrocytic P2Y1R signaling. Blockade of N-methyl-D-aspartic acid (NMDA) receptors, but not metabotropic receptors, and the GluN2B subtype of NMDA receptors abolished the antidepressant effect of low-dose LPS. GluN2B knockdown also abolished the reversal effect of low-dose LPS on CUS-induced depression-like behaviors and impairment of dentate gyrus ERK1/2-BDNF signaling. Moreover, chelating intracellular CA2+ or suppressing CA2+/calmodulin-dependent protein kinase II (CaMKII) abolished the reversal effect of low-dose LPS on chronic unpredictable stress (CUS)-induced depression-like behaviors and impairment of dentate gyrus ERK1/2-BDNF signaling. Additionally, suppression of protein kinase A (PKA) and protein kinase C (PKC) did not abolish the antidepressant effect of low-dose LPS. These findings demonstrate that activation of the GluN2B-CaMKII signaling cascade in the dentate gyrus is required for the rapid antidepressant action of low-dose LPS, as well as the reversal effect of LPS on impaired ERK1/2-BDNF signaling in the hippocampus, which may help to elucidate the microglial deficiency hypothesis of depression.

Keywords

CaMKII; Depression; GluN2B; Hippocampus; Microglia.

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