Downregulation of neuronal DRD2 drives microglia synaptic pruning and results in cognitive deficits by promoting CCL2 release in a rat model of chronic migraine

Chronic migraine (CM) is a disabling neurological condition increasingly recognized for its link to cognitive deficits and a potential higher dementia risk. Although microglia-mediated synaptic pruning has been associated with cognitive decline, its role in CM is not fully understood. The dopamine D2 receptor (DRD2), crucial for cognitive function, has been shown to affect synaptic pruning. This study investigates how DRD2 signaling influences microglial phagocytosis and synaptic integrity in CM. We established a chronic migraine model with repeated dural administration of inflammatory soup (IS), significantly reducing hippocampal DRD2, decreasing Postsynaptic density protein 95 (PSD95) levels, increasing microglial phagocytosis, and impairing spatial and non-spatial memory. These effects were lessened by administering the DRD2 agonist quinpirole. Transcriptomic analysis revealed that DRD2 deficiency causes overexpression of C-C motif chemokine ligand 2 (CCL2). Further mechanistic studies showed that DRD2 regulates microglial phagocytic activation through CCL2 and its receptor CCR2. This is the first identification of a "neuronal DRD2-CCL2-microglial phagocytosis-synaptic loss" axis, highlighting the active role of neuronal DRD2 in regulating synaptic pruning in CM. These findings suggest new treatment options for reducing cognitive impairment in CM by targeting the DRD2-CCL2-CCR2 pathway.