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

A Corrigendum to this article was published on 13 May 2015

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.

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.

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Figure 1: Synaptic organization of 2-arachidonoylglycerol-mediated retrograde signalling molecules in the CA1 region of the hippocampus.
Figure 2: CB1-mediated tonic and phasic inhibition.
Figure 3: Schematic illustration of molecular mechanisms for endocannabinoid-mediated synaptic plasticity.
Figure 4: Endocannabinoids, exocannabinoids, and network oscillations.
Figure 5: Bidirectional effects of cannabinoids and seizures.

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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.

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Correspondence to Ivan Soltesz.

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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).

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Soltesz, I., Alger, B., Kano, M. et al. Weeding out bad waves: towards selective cannabinoid circuit control in epilepsy. Nat Rev Neurosci 16, 264–277 (2015). https://doi.org/10.1038/nrn3937

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