Cannabidiol modulates excitatory-inhibitory ratio to counter hippocampal hyperactivity


Evan C. Rosenberg, Simon Chamberland, Michael Bazelot,Erica R. Nebet, Xiaohan Wang, Sam McKenzie, Swati Jain,Stuart Greenhill, Max Wilson, Nicole Marley, Alejandro Salah, Shanice Bailey, Pabitra Hriday Patra, Rebecca Rose, Nicolas Chenouard, Simon(e) D. Sun, Drew Jones, Gyorgy Buzsaki, Orrin Devinsky, Gavin Woodhall, Helen E. Scharfman, Benjamin J. Whalley, Richard W. Tsien


April 19, 2023


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 GABAARg2 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.


DOI: 10.1016/j.neuron.2023.01.018


Rosenberg, E. C., Chamberland, S., Bazelot, M., Nebet, E. R., Wang, X., McKenzie, S., … & Tsien, R. W. (2023). Cannabidiol modulates excitatory-inhibitory ratio to counter hippocampal hyperactivity. Neuron.