JZL184

Neuroinflammation is a key feature of Parkinson's disease (PD). The cannabinoid receptor type 2 (CB2R) is expressed by cells of the innate and adaptive immune systems. Inhibition of monoacylglycerol lipase (MAGL) with JZL184 increases the levels of the endocannabinoid 2-arachidonoylglycerol (2-AG), which is neuroprotective for dopaminergic neurons. The aim of this study was to determine whether the neuroprotective effect of MAGL inhibition is mediated by CB2R activation on specific immune cell populations. Experimental parkinsonism was induced by chronic administration of MPTP and probenecid. A specific increase in CD4⁺ T cell infiltration was detected in the midbrain of parkinsonian mice and was reduced by administration of JZL184. JZL184 had no effect in CB2R KO mice, suggesting that CB2R is required for neuroprotection. In the brain, CB2R expression was restricted to myeloid cells and lymphocytes, and increased in microglia under parkinsonian conditions. Administration of a central CB2R agonist, JWH133, exerted a beneficial effect similar to that of JZL184, whereas the peripheral agonist RO304 lacked neuroprotective activity. These results were confirmed using chimeric mice. In silico analysis, showed that transcripts related to 2-AG biosynthesis are downregulated in the midbrain microglia from PD patients. Our results show that activation of CB2R in the brain prevents nigrostriatal degeneration, CD4⁺ T cell infiltration and TNFα production in the midbrain of parkinsonian mice. The reduced 2-AG signaling in microglia from PD patients suggests that activation of microglial CB2R may be an interesting strategy for the treatment of PD.

We report here that microglia exert a surprisingly discrete but functionally critical influence on synaptic plasticity in the mouse hippocampus. Treatment of adult male mice with colony-stimulating factor 1 receptor antagonist PLX5622 (PLX), with resultant depletion of forebrain microglia, did not disturb basal synaptic transmission at four synaptic connections in the hippocampus. Long-term potentiation (LTP) was also intact for three of these sites, but the singular, endocannabinoid-dependent form of LTP expressed by lateral perforant path (LPP) input to the dentate gyrus (DG) was severely impaired. The LPP–LTP defect occurred in conjunction with a pronounced increase in DG (but not neocortical) levels of 2-arachidonoylglycerol (2-AG), the retrograde (spine-to-terminal) endocannabinoid messenger that initiates LPP–LTP. Despite this, concentrations of the 2-AG synthetic enzyme diacylglycerol lipase were not affected by PLX treatment. Synaptic levels of the cannabinoid type 1 receptor, which mediates 2-AG effects on LPP–LTP, were similarly unaffected. Prior work has implicated the LPP in episodic memory. We determined that the LPP–LTP impairment in PLX-treated mice was accompanied by a failure to acquire the three basic elements of an episode: the identities, locations, and presentation order for a collection of olfactory cues. Treatment with JZL184, which inhibits the 2-AG degradative enzyme monoglyceride lipase, restored both LPP–LTP and episodic “What” encoding in PLX-treated mice. We conclude that microglia selectively regulate endocannabinoid transmission at the LPP→DG synapse and thereby potently influence synaptic plasticity at the initial stage of a corticohippocampal circuit that is critical for episodic memory.