Importance of glial CB1R in the regulation of neuromuscular repair

Intricate and extended mechanisms are in place to allow for repair following injuries of the peripheral nervous system (PNS), particularly at the neuromuscular junction (NMJ). Type 1 endocannabinoid receptors (CB1R) may be involved in the repair process owing to their presence in the PNS and at the NMJ and given their role in axonal growth and neuronal plasticity. Owing to the role of perisynaptic Schwann cells, glial cells at the NMJ, in the regulation of NMJ repair following injury, we postulate that CB1R participate in NMJ denervation and reinnervation processes and that this regulation may be mediated by glial cells. To this end, we performed nerve injury and examined the impact of CBR1 blockade on NMJ denervation and reinnervation. CB1R were either blocked with the antagonist AM-251 or using CB1R-KO (full KO) and GFAP-CB1R-KO (glial KO). Our results show that CB1R blockade with AM251 leads to an acceleration of the denervation process indicated by an increased percentage of denervated NMJ and an increased expression of MAC-2, a phagocytic indicator, also observed in CB1R-KO and GFAP-CB1-KO mice. On the other hand, CB1R blockade caused a delay in reinnervation. Considering our results and the similar phenomenon observed in CB1R-KO and GFAP-CB1R-KO, glial CB1R are heavily involved in NMJ plasticity occurring during denervation and reinnervation. These results open a new possibility to target endocannabinoids receptors to facilitate reinnervation after injury or in the context of neurodegenerative diseases such as amyotrophic lateral sclerosis.