Cannabidiol modulates excitatory-inhibitory ratio to counter hippocampal hyperactivity


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.

Publication DOI:
Divisions: College of Health & Life Sciences > Aston Pharmacy School
College of Health & Life Sciences > Aston Institute of Health & Neurodevelopment (AIHN)
College of Health & Life Sciences
College of Health & Life Sciences > Clinical and Systems Neuroscience
Additional Information: 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).
Uncontrolled Keywords: G-protein-coupled receptor,GABA receptors,cannabidiol,cannabinoid,epilepsy,hippocampus,inhibition,lysophosphatidylinositol,neuromodulation,seizure,Neuroscience(all)
Publication ISSN: 1097-4199
Last Modified: 23 May 2024 07:20
Date Deposited: 02 Mar 2023 10:06
Full Text Link:
Related URLs: https://www.sci ... 0661?via%3Dihub (Publisher URL)
http://www.scop ... tnerID=8YFLogxK (Scopus URL)
PURE Output Type: Article
Published Date: 2023-04-19
Published Online Date: 2023-02-13
Accepted Date: 2023-01-20
Authors: Rosenberg, Evan C.
Chamberland, Simon
Bazelot, Michael
Nebet, Erica R.
Wang, Xiaohan
McKenzie, Sam
Jain, Swati
Greenhill, Stuart (ORCID Profile 0000-0002-5038-5258)
Wilson, Max
Marley, Nicole
Salah, Alejandro
Bailey, Shanice
Patra, Pabitra Hriday
Rose, Rebecca
Chenouard, Nicolas
Sun, Simón(e) D.
Jones, Drew
Buzsáki, György
Devinsky, Orrin
Woodhall, Gavin (ORCID Profile 0000-0003-1281-9008)
Scharfman, Helen E.
Whalley, Benjamin J.
Tsien, Richard W.



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