| First Author | Feng L | Year | 2023 |
| Journal | Exp Neurol | Volume | 359 |
| Pages | 114230 | PubMed ID | 36162511 |
| Mgi Jnum | J:336520 | Mgi Id | MGI:7345299 |
| Doi | 10.1016/j.expneurol.2022.114230 | Citation | Feng L, et al. (2022) Loss of cannabinoid receptor 2 promotes alpha-Synuclein-induced microglial synaptic pruning in nucleus accumbens by modulating the pCREB-c-Fos signaling pathway and complement system. Exp Neurol 359:114230 |
| abstractText | The disruption of nucleus accumbens (NAc) function impacts mood and learning behavior in alpha-Synucleinopathy, in which microglial synaptic pruning plays a pivotal role in modulating the neuropathologic progression. Available literature documents that in microglia, the activation of cannabinoid receptor 2 (CB2R) decreases inflammation, but it remains obscured regarding the roles of CB2R in microglia-mediated synaptic pruning in the NAc during the neuropathological progression of alpha-Synucleinopathy. We adopted the fibrillar alpha-Synuclein (alpha-Syn) treatment to characterize the effect of genetic CB2R deletion on microglial function and the signaling pathway. CB2R knockout (CB2(-/-)) mice and wild-type (CB2(+/+)) mice were divided into the alpha-Syn or saline treatment groups. Biochemical and microscopy approaches, including immunofluorescence, real-time PCR, and western blotting, were employed to assess the changes in homeostasis of synaptic pruning in NAc under the alpha-Syn-induced microglia. Moreover, the underlying mechanisms of CB2R on alpha-Syn induced microglial activity was assessed in vitro. After the injection of alpha-Syn into the NAc, distinct microglial morphological changes and M1 phenotype transformation were observed between CB2(-/-) and CB2(+/+) mice. Meanwhile, after the alpha-Syn treatment, CB2(-/-) mice showed an increased upregulation of CD68 protein and IL-1beta mRNA but decreased brain-derived neurotrophic factor (BDNF) and TGF-beta mRNA compared with CB2(+/+) mice. Additionally, CB2(-/-) microglia after the treatment showed a highly enriched complement 3a receptor (C3aR) producing excessive pruning of cholinergic synapses but less engulfment of dopaminergic synapses. Mechanistically, the loss of CB2R function in the alpha-Syn stimulation triggered c-Fos activation in microglia, but not in neurons. Further inhibition of microglial CB2R functions under alpha-Syn stimulation activated the phosphorylated cAMP-response element-binding protein (pCREB)-c-Fos, which was closely related to the C3aR upregulation. Our results reveal a critical and mechanistic role of CB2R in altering the microglial function and its value in the homeostasis of synaptic circuits in the NAc under the alpha-Syn pathology. |
