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 Woodhall; Helen E. Scharfman; Benjamin J. Whalley; Richard W. Tsien

doi:10.1016/j.neuron.2023.01.018

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 journal › Article › peer-review

Abstract

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 language	English
Pages (from-to)	1282-1300.e8
Number of pages	28
Journal	Neuron
Volume	111
Issue number	8
Early online date	13 Feb 2023
DOIs	https://doi.org/10.1016/j.neuron.2023.01.018
Publication status	Published - 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 (https://creativecommons.org/licenses/by-nc-nd/4.0/).

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).

Keywords

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

Access to Document

10.1016/j.neuron.2023.01.018Licence: CC BY-NC-ND 4.0

Rosenbergetal_2023_VoR
Copyright © 2023 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (https://creativecommons.org/licenses/by-nc-nd/4.0/)
Final published version, 6.1 MBLicence: CC BY-NC-ND 4.0

Cite this

Rosenberg, E. C., Chamberland, S., Bazelot, M., Nebet, E. R., Wang, X., McKenzie, S., Jain, S., Greenhill, S., Wilson, M., Marley, N., Salah, A., Bailey, S., Patra, P. H., Rose, R., Chenouard, N., Sun, S. D., Jones, D., Buzsáki, G., Devinsky, O., ... Tsien, R. W. (2023). Cannabidiol modulates excitatory-inhibitory ratio to counter hippocampal hyperactivity. Neuron, 111(8), 1282-1300.e8. https://doi.org/10.1016/j.neuron.2023.01.018

@article{5b0b2a1fa83445ba83156c1383e6353d,

title = "Cannabidiol modulates excitatory-inhibitory ratio to counter hippocampal hyperactivity",

abstract = "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-GPR55signaling at inhibitory synapses and in epileptogenesis remains underexplored. We found that LPI transientlyincreased hippocampal CA3-CA1 excitatory presynaptic release probability and evoked synaptic strength inWT 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{\textquoteright}s pro-excitatory effects. We propose that CBD exerts potential anti-seizure effects by blocking LPI{\textquoteright}s synaptic effects and dampening hyperexcitability.",

keywords = "G-protein-coupled receptor, GABA receptors, cannabidiol, cannabinoid, epilepsy, hippocampus, inhibition, lysophosphatidylinositol, neuromodulation, seizure",

author = "Rosenberg, {Evan C.} and Simon Chamberland and Michael Bazelot and Nebet, {Erica R.} and Xiaohan Wang and Sam McKenzie and Swati Jain and Stuart Greenhill and Max Wilson and Nicole Marley and Alejandro Salah and Shanice Bailey and Patra, {Pabitra Hriday} and Rebecca Rose and Nicolas Chenouard and Sun, {Sim{\'o}n(e) D.} and Drew Jones and Gy{\"o}rgy Buzs{\'a}ki and Orrin Devinsky and Gavin Woodhall and Scharfman, {Helen E.} and Whalley, {Benjamin J.} and Tsien, {Richard W.}",

note = "Copyright {\textcopyright} 2023 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (https://creativecommons.org/licenses/by-nc-nd/4.0/). 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 Qu{\'e}bec - Sant{\'e}, and a K99/R00 Pathway to Independence Award from NIMH (1K99MH126157-01).",

year = "2023",

month = apr,

day = "19",

doi = "10.1016/j.neuron.2023.01.018",

language = "English",

volume = "111",

pages = "1282--1300.e8",

journal = "Neuron",

issn = "0896-6273",

publisher = "Cell Press",

number = "8",

}

Rosenberg, EC, Chamberland, S, Bazelot, M, Nebet, ER, Wang, X, McKenzie, S, Jain, S, Greenhill, S, Wilson, M, Marley, N, Salah, A, Bailey, S, Patra, PH, Rose, R, Chenouard, N, Sun, SD, Jones, D, Buzsáki, G, Devinsky, O, Woodhall, G, Scharfman, HE, Whalley, BJ & Tsien, RW 2023, 'Cannabidiol modulates excitatory-inhibitory ratio to counter hippocampal hyperactivity', Neuron, vol. 111, no. 8, pp. 1282-1300.e8. https://doi.org/10.1016/j.neuron.2023.01.018

TY - JOUR

T1 - Cannabidiol modulates excitatory-inhibitory ratio to counter hippocampal hyperactivity

AU - Rosenberg, Evan C.

AU - Chamberland, Simon

AU - Bazelot, Michael

AU - Nebet, Erica R.

AU - Wang, Xiaohan

AU - McKenzie, Sam

AU - Jain, Swati

AU - Greenhill, Stuart

AU - Wilson, Max

AU - Marley, Nicole

AU - Salah, Alejandro

AU - Bailey, Shanice

AU - Patra, Pabitra Hriday

AU - Rose, Rebecca

AU - Chenouard, Nicolas

AU - Sun, Simón(e) D.

AU - Jones, Drew

AU - Buzsáki, György

AU - Devinsky, Orrin

AU - Woodhall, Gavin

AU - Scharfman, Helen E.

AU - Whalley, Benjamin J.

AU - Tsien, Richard W.

N1 - Copyright © 2023 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (https://creativecommons.org/licenses/by-nc-nd/4.0/). 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).

PY - 2023/4/19

Y1 - 2023/4/19

N2 - 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-GPR55signaling at inhibitory synapses and in epileptogenesis remains underexplored. We found that LPI transientlyincreased hippocampal CA3-CA1 excitatory presynaptic release probability and evoked synaptic strength inWT 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.

AB - 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-GPR55signaling at inhibitory synapses and in epileptogenesis remains underexplored. We found that LPI transientlyincreased hippocampal CA3-CA1 excitatory presynaptic release probability and evoked synaptic strength inWT 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.

KW - G-protein-coupled receptor

KW - GABA receptors

KW - cannabidiol

KW - cannabinoid

KW - epilepsy

KW - hippocampus

KW - inhibition

KW - lysophosphatidylinositol

KW - neuromodulation

KW - seizure

UR - https://www.sciencedirect.com/science/article/pii/S0896627323000661?via%3Dihub

UR - http://www.scopus.com/inward/record.url?scp=85149961252&partnerID=8YFLogxK

U2 - 10.1016/j.neuron.2023.01.018

DO - 10.1016/j.neuron.2023.01.018

M3 - Article

SN - 0896-6273

VL - 111

SP - 1282-1300.e8

JO - Neuron

JF - Neuron

IS - 8

ER -

Cannabidiol modulates excitatory-inhibitory ratio to counter hippocampal hyperactivity

Abstract

Bibliographical note

Keywords

Access to Document

Other files and links

Fingerprint

Cite this