Nahir B, Bhatia C, Frazier CJ. Presynaptic inhibition of excitatory afferents to hilar mossy cells.

Non-technical summary Communication between many types of neurons in the brain can be strongly modulated by activation of cannabinoid receptors. Such receptors are likely to be responsible for mediating many of the effects of marijuana on the central nervous system, and yet they can also be activated by both endogenous and synthetic compounds. Here we describe a novel effect of two well-known cannabinoid receptor ligands on spontaneous synaptic transmission in an area of the brain that is essential for the formation of new memories, and that is strongly implicated in the aetiology of temporal lobe epilepsy. Interestingly, this effect appears to be receptor dependent, and yet does not require any currently known cannabinoid receptor. Further exploration of this phenomenon may help us better understand how spontaneous release of neurotransmitters is regulated in the central nervous system, and could also ultimately help to inform new strategies for therapeutic regulation of cortical excitability.Abstract We report a novel excitatory effect of cannabinoid agonists on action potential-independent GABAergic transmission in the rat dentate gyrus. Specifically, we find that both WIN55,212-2 and anandamide increase the frequency of miniature IPSCs (mIPSCs) recorded from hilar mossy cells without altering event amplitude, area, rise time, or decay. The effect of WIN55,212-2 on mIPSCs is insensitive to AM251 and preserved in CB1 −/− animals, indicating that it does not depend on activation of CB1 receptors. It is also insensitive to AM630 and unaffected by capsazepine suggesting that neither CB2 nor TRPV1 receptors are involved. Further, it is blocked by pre-incubation in suramin and by a selective protein kinase A inhibitor (H-89), and is mimicked (and occluded) by bath application of forskolin. Similar CB1 receptor-independent facilitation of exocytosis is not apparent when recording evoked IPSCs in the presence of AM251, suggesting that the exocytotic mechanism that produces WIN55,212-2 sensitive mIPSCs is distinct from that which produces CB1 sensitive and action potential-dependent release. Despite clear independence from action potentials, WIN55,212-2 mediated facilitation of mIPSCs requires calcium, and yet is insensitive to chelation of calcium in the postsynaptic cell. Finally, we demonstrate that both bath application of 2-arachidonoylglycerol (2-AG) and depolarization-induced release of endogenous cannabinoids have minimal effect on mIPSC frequency. Cumulatively, our results indicate that cannabinoid ligands can selectively facilitate action potential-independent exocytosis of GABA in the rat dentate gyrus, and further emphasize that this new cannabinoid sensitive signalling system is distinct from previously described CB1 receptor-dependent systems in numerous respects.M. E. Hofmann and C. Bhatia contributed equally to this work.