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, Simón(e) D. Sun, Drew Jones, György Buzsáki, Orrin Devinsky, Gavin WoodhallHelen E. Scharfman, Benjamin J. Whalley, Richard W. Tsien*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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.
Original languageEnglish
Pages (from-to)1282-1300.e8
Number of pages28
Issue number8
Early online date13 Feb 2023
Publication statusPublished - 19 Apr 2023

Bibliographical note

Copyright © 2023 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (

Funding: This work is supported by funding from the Ruth L. Kirschstein National Research Service Awards (NRSA) for individual pre-doctoral MD/PhDs (F30 NS100293), the NYU MSTP training grant (T32GM007308), and grants to R.W.T. from the NIMH (5R37MH071739), NIDA (DA040484-01), the Simons Foundation, and the Vulnerable Brain Project. S.C., A.S., and O.D. are supported by funding from FACES, Finding A Cure for Epilepsy and Seizures. S.C. is supported by a Charles H. Revson Senior Fellowship in Biomedical Science, Andrew Ellis and Emily Segal Investigator Grant from the Brain and Behavior Research Foundation, postdoctoral fellowship from the Fonds de Recherche du Québec - Santé, and a K99/R00 Pathway to Independence Award from NIMH (1K99MH126157-01).


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


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