Cannabidiol targets a modulatory system for excitatory-inhibitory synaptic coordination, contributing to its anti-seizure action

Cannabidiol (CBD), a non-euphoric component of cannabis, reduces seizures in multiple forms of pediatric epilepsy, but the mechanism(s) of anti-seizure action remain unclear. In one leading model, CBD acts at glutamatergic axon terminals, blocking pro-excitatory actions of an endogenous membrane phospholipid, lysophosphatidylinositol (LPI), at the G protein-coupled receptor GPR55. However, the impact of LPI-GPR55 signaling at inhibitory synapses and in epileptogenesis remains underexplored. We found that LPI transiently increased hippocampal CA3→CA1 excitatory presynaptic release probability and evoked synaptic strength in WT mice, while attenuating inhibitory postsynaptic strength by decreasing GABAARγ2 and gephyrin puncta. Effects of LPI at both excitatory and inhibitory synapses were eliminated by CBD pretreatment and absent after GPR55 deletion. Acute pentylenetrazole-induced seizures elevated levels of GPR55 and LPI, and chronic lithium pilocarpine-induced epileptogenesis potentiated the pro-excitatory effects of LPI. We propose that CBD exerts potential therapeutic effect both by blocking synaptic effects of LPI and dampening hyperexcitability. ### Competing Interest Statement GW Research Ltd (Cambridge, UK) supplied plant-derived highly purified cannabidiol to R.W.T., M.B., B.W., and G.L.W. for experimental use, and provided funding for animal maintenance for G.L.W. B.W. is an employee of GW Research Ltd, now part of Jazz Pharmaceuticals Inc., Cambridge, UK. M.B. was formerly an employee of GW Research Ltd, now part of Jazz Pharmaceuticals Inc., Cambridge, UK. Orrin Devinsky receives grant support from NINDS, NIMH, MURI, CDC and NSF. He has equity and/or compensation from the following companies: Privateer Holdings, Tilray, Receptor Life Sciences, Qstate Biosciences, Tevard, Empatica, Engage, Egg Rock/Papa & Barkley, Rettco, SilverSpike, and California Cannabis Enterprises (CCE). He has received consulting fees from GW Research Ltd, Cavion, and Zogenix. He holds patents for the use of cannabidiol in treating neurological disorders, but these are owned by GW Pharmaceuticals and he has waived any financial stake in these patents. The other authors have no other conflicts of interest to report