Review Article | Published:

Weeding out bad waves: towards selective cannabinoid circuit control in epilepsy

Nature Reviews Neuroscience volume 16, pages 264277 (2015) | Download Citation

  • A Corrigendum to this article was published on 13 May 2015

Abstract

Endocannabinoids are lipid-derived messengers, and both their synthesis and breakdown are under tight spatiotemporal regulation. As retrograde signalling molecules, endocannabinoids are synthesized postsynaptically but activate presynaptic cannabinoid receptor 1 (CB1) receptors to inhibit neurotransmitter release. In turn, CB1-expressing inhibitory and excitatory synapses act as strategically placed control points for activity-dependent regulation of dynamically changing normal and pathological oscillatory network activity. Here, we highlight emerging principles of cannabinoid circuit control and plasticity, and discuss their relevance for epilepsy and related comorbidities. New insights into cannabinoid signalling may facilitate the translation of the recent interest in cannabis-related substances as antiseizure medications to evidence-based treatment strategies.

Key points

  • Endocannabinoids are lipid-derived signalling molecules that are synthesized postsynaptically to activate presynaptic cannabinoid receptors 1 (CB1) receptors to influence diverse brain functions; CB1 receptors can also be activated by exogenous cannabinoids, such as the phytocannabinoid, Δ9-tetrahydrocannabinol (Δ9-THC) or THC.

  • Although CB1 receptors are abundantly expressed in the brain, their expression is highly specific at the microscopic scale; they are present primarily at the axon terminals of specific inhibitory and excitatory neuronal subtypes.

  • Endocannabinoids inhibit neurotransmitter release on various timescales, including inhibition of tonic (baseline) release and various types of activity-dependent short- and long-term plasticity.

  • Neuronal circuits display various behavioural state-dependent network oscillations, and emerging principles of cannabinoid modulation of network rhythms have important implications for epilepsy and other neurological and psychiatric disorders that involve pathologically altered neuronal oscillations.

  • Safe and side effect-free future cannabinoid-based medications for epilepsy and related disorders will probably target cannabinoid signalling molecules with high cell type, temporal and spatial selectivity.

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Acknowledgements

The authors thank J. G. Malpeli for comments on the manuscript and M. Uchigashima for Figure 1c. This work was supported by a US National Institutes of Health grant (NS74432 to I.S.) and Grants-in-Aid for Scientific Research (23500466 to T.O.-S. and 25000015 to M.K.) from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

Author information

Affiliations

  1. Department of Anatomy and Neurobiology, University of California, Irvine, California 92697, USA.

    • Ivan Soltesz
    •  & Sang-Hun Lee
  2. Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.

    • Bradley E. Alger
  3. Department of Neurophysiology, Graduate School of Medicine, The University of Tokyo, Tokyo 113–0033, Japan.

    • Masanobu Kano
  4. Section on Synaptic Pharmacology, Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, US National Institutes of Health, Bethesda, Maryland 20892, USA.

    • David M. Lovinger
  5. Department of Impairment Study, Graduate School of Medical Science, Kanazawa University, Kanazawa 920–0942, Japan.

    • Takako Ohno-Shosaku
  6. Department of Anatomy, Hokkaido University Graduate School of Medicine, Sapporo 060–8638, Japan.

    • Masahiko Watanabe

Authors

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Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Ivan Soltesz.

Glossary

Endocannabinoids

Endogenous molecules, typically with marijuana-mimetic activity, that primarily act on type 1 and 2 cannabinoid receptors.

Epilepsy

A neurological disorder characterized by a predisposition to recurrent, unprovoked seizures.

GABAergic interneurons

Locally projecting neurons that synthesize, store and release GABA as a neurotransmitter.

GABAergic cell

Synthesizes, stores and releases GABA as a neurotransmitter.

Retrograde signalling molecule

An endogenous signalling messenger molecule that is synthesized in, and released from, postsynaptic cells and acts on presynaptic sites.

Nested gamma oscillations

Short repetitive bursts of gamma waves (30–80 Hz) that often take place during (that is, nested within) the slower theta rhythm (5–10 Hz) at a particular phase of the theta oscillatory cycle.

Epileptogenesis

The process by which the brain develops epilepsy (for example, after an insult such as head trauma).

About this article

Publication history

Published

DOI

https://doi.org/10.1038/nrn3937

Further reading