Exercise improved P2Y12-regulated microglial dynamics during stroke via endocannabinoid signaling

Microglia are vigilant housekeepers in the adult brain, they continually extend and retract their processes to survey their microenvironment. In a dependent manner involving P2Y12 receptors, microglia undergo morphological and functional changes to form microglia-neuron contacts to protect neurons from damage. By using in vivo two-photon imaging, we found that physical exercise (PE) upregulated microglial P2Y12 expression, increased microglial dynamics, and promoted the microglia contacting with neurons in a mouse model of transit middle cerebral artery occlusion (tMCAO). As a result, microglial processes inhibited neuronal calcium overloads, protected against damage of the neuronal mitochondria and synaptic structure. Inhibition of P2Y12 by PSB0739 abolished the protection induced by PE. Mechanistically, we found PE increased the cannabinoid receptor 2 (CBR2) in microglia, and administration of AM630, a CBR2 antagonist, decreased P2Y12R expression and abolished PE-mediated effects. These findings identified endocannabinoid signaling may as the critical regulator of the PE-induced P2Y12-mediated effect whereby PE increased the endocannabinoid system to regulate purinergic signaling, further inducing microglial processes at microglia-neuron contacts to monitor and protect neuronal functioning.