Cannabidiol modulates excitatory-inhibitory ratio to counter hippocampal hyperactivity

. 2023 Feb 10;S0896-6273(23)00066-1.

doi: 10.1016/j.neuron.2023.01.018.

Online ahead of print.


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Evan C Rosenberg et al.




Cannabidiol (CBD), a non-euphoric component of cannabis, reduces seizures in multiple forms of pediatric epilepsies, but the mechanism(s) of anti-seizure action remain unclear. In one leading model, CBD acts at glutamatergic axon terminals, blocking the 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 GABAA2 and gephyrin puncta. LPI effects at excitatory and inhibitory synapses were eliminated by CBD pre-treatment and absent after GPR55 deletion. Acute pentylenetrazole-induced seizures elevated GPR55 and LPI levels, and chronic lithium-pilocarpine-induced epileptogenesis potentiated LPI’s pro-excitatory effects. We propose that CBD exerts potential anti-seizure effects by blocking LPI’s synaptic effects and dampening hyperexcitability.


G-protein-coupled receptor; GABA receptors; cannabidiol; cannabinoid; epilepsy; hippocampus; inhibition; lysophosphatidylinositol; neuromodulation; seizure.

Conflict of interest statement

Declaration of interests GW Research Ltd (Cambridge, UK) supplied plant-derived highly purified CBD to R.W.T., M.B., B.J.W., and G.W. for experimental use and provided funding for animal maintenance for G.W. B.J.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. O.D. 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 CBD in treating neurological disorders, but these are owned by GW Research Ltd, and he has waived any financial stake in these patents.

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