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.
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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Piomelli, D., Astarita, G. & Rapaka, R. A neuroscientist's guide to lipidomics. Nature Rev. Neurosci. 8, 743–754 (2007).
Kano, M., Ohno-Shosaku, T., Hashimotodani, Y., Uchigashima, M. & Watanabe, M. Endocannabinoid-mediated control of synaptic transmission. Physiol. Rev. 89, 309–380 (2009).
Katona, I. & Freund, T. F. Endocannabinoid signaling as a synaptic circuit breaker in neurological disease. Nature Med. 14, 923–930 (2008).
Heifets, B. D. & Castillo, P. E. Endocannabinoid signaling and long-term synaptic plasticity. Annu. Rev. Physiol. 71, 283–306 (2009).
Mechoulam, R. & Parker, L. A. The endocannabinoid system and the brain. Annu. Rev. Psychol. 64, 21–47 (2013).
Devinsky, O. et al. Cannabidiol: pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders. Epilepsia 55, 791–802 (2014).
Armstrong, C., Morgan, R. J. & Soltesz, I. Pursuing paradoxical proconvulsant prophylaxis for epileptogenesis. Epilepsia 50, 1657–1669 (2009).
Katona, I. & Freund, T. F. Multiple functions of endocannabinoid signaling in the brain. Annu. Rev. Neurosci. 35, 529–558 (2012).
Hofmann, M. E. & Frazier, C. J. Marijuana, endocannabinoids, and epilepsy: potential and challenges for improved therapeutic intervention. Exp. Neurol. 244, 43–50 (2013).
Ohno-Shosaku, T. & Kano, M. Endocannabinoid-mediated retrograde modulation of synaptic transmission. Curr. Opin. Neurobiol. 29, 1–8 (2014).
Alger, B. E. Seizing an opportunity for the endocannabinoid system. Epilepsy Curr. 14, 272–276 (2014).
Varga, C., Golshani, P. & Soltesz, I. Frequency-invariant temporal ordering of interneuronal discharges during hippocampal oscillations in awake mice. Proc. Natl Acad. Sci. USA 109, E2726–E2734 (2012).
Ylinen, A. et al. Sharp wave-associated high-frequency oscillation (200 Hz) in the intact hippocampus: network and intracellular mechanisms. J. Neurosci. 15, 30–46 (1995).
Siapas, A. G. & Wilson, M. A. Coordinated interactions between hippocampal ripples and cortical spindles during slow-wave sleep. Neuron 21, 1123–1128 (1998).
Eschenko, O., Ramadan, W., Mölle, M., Born, J. & Sara, S. J. Sustained increase in hippocampal sharp-wave ripple activity during slow-wave sleep after learning. Learn. Mem. 15, 222–228 (2008).
Bragin, A., Wilson, C. L., Almajano, J., Mody, I. & Engel, J. Jr. High-frequency oscillations after status epilepticus: epileptogenesis and seizure genesis. Epilepsia 45, 1017–1023 (2004).
Klein, T. W. et al. The cannabinoid system and immune modulation. J. Leukoc. Biol. 74, 486–496 (2003).
Lee, S.-H., Földy, C. & Soltesz, I. Distinct endocannabinoid control of GABA release at perisomatic and dendritic synapses in the hippocampus. J. Neurosci. 30, 7993–8000 (2010). This study provides evidence of cell type-specific eCB-mediated control of GABA release at perisomatic and dendritic synapses.
Katona, I. et al. Presynaptically located CB1 cannabinoid receptors regulate GABA release from axon terminals of specific hippocampal interneurons. J. Neurosci. 19, 4544–4558 (1999).
Katona, I. et al. Molecular composition of the endocannabinoid system at glutamatergic synapses. J. Neurosci. 26, 5628–5637 (2006).
Bezaire, M. J. & Soltesz, I. Quantitative assessment of CA1 local circuits: knowledge base for interneuron-pyramidal cell connectivity. Hippocampus 23, 751–785 (2013).
Armstrong, C. & Soltesz, I. Basket cell dichotomy in microcircuit function. J. Physiol. 590, 683–694 (2012).
Hu, H., Gan, J. & Jonas, P. Fast-spiking, parvalbumin+ GABAergic interneurons: from cellular design to microcircuit function. Science 345, 1255263 (2014).
Mackie, K. Distribution of cannabinoid receptors in the central and peripheral nervous system. Handb. Exp. Pharmacol. 168, 299–325 (2005).
Kawamura, Y. et al. The CB1 cannabinoid receptor is the major cannabinoid receptor at excitatory presynaptic sites in the hippocampus and cerebellum. J. Neurosci. 26, 2991–3001 (2006).
Stella, N., Schweitzer, P. & Piomelli, D. A second endogenous cannabinoid that modulates long-term potentiation. Nature 388, 773–778 (1997).
Tanimura, A. et al. The endocannabinoid 2-arachidonoylglycerol produced by diacylglycerol lipase α mediates retrograde suppression of synaptic transmission. Neuron 65, 320–327 (2010).
Gao, Y. et al. Loss of retrograde endocannabinoid signaling and reduced adult neurogenesis in diacylglycerol lipase knock-out mice. J. Neurosci. 30, 2017–2024 (2010). References 27 and 28 show that 2-AG, which is produced by DAGLα, mediates retrograde suppression of synaptic transmission.
Suárez, J. et al. Distribution of diacylglycerol lipase α, an endocannabinoid synthesizing enzyme, in the rat forebrain. Neuroscience 192, 112–131 (2011).
Yoshida, T. et al. Localization of diacylglycerol lipase-α around postsynaptic spine suggests close proximity between production site of an endocannabinoid, 2-arachidonoyl-glycerol, and presynaptic cannabinoid CB1 receptor. J. Neurosci. 26, 4740–4751 (2006).
Hashimotodani, Y. et al. Phospholipase Cβ serves as a coincidence detector through its Ca2+ dependency for triggering retrograde endocannabinoid signal. Neuron 45, 257–268 (2005).
Abe, T. et al. Molecular characterization of a novel metabotropic glutamate receptor mGluR5 coupled to inositol phosphate/Ca2+ signal transduction. J. Biol. Chem. 267, 13361–13368 (1992).
Watanabe, M. et al. Patterns of expression for the mRNA corresponding to the four isoforms of phospholipase Cβ in mouse brain. Eur. J. Neurosci. 10, 2016–2025 (1998).
Fukaya, M. et al. Predominant expression of phospholipase Cβ1 in telencephalic principal neurons and cerebellar interneurons, and its close association with related signaling molecules in somatodendritic neuronal elements. Eur. J. Neurosci. 28, 1744–1759 (2008).
Lujan, R., Nusser, Z., Roberts, J. D., Shigemoto, R. & Somogyi, P. Perisynaptic location of metabotropic glutamate receptors mGluR1 and mGluR5 on dendrites and dendritic spines in the rat hippocampus. Eur. J. Neurosci. 8, 1488–1500 (1996).
Dinh, T. P. et al. Brain monoglyceride lipase participating in endocannabinoid inactivation. Proc. Natl Acad. Sci. USA 99, 10819–10824 (2002).
Hashimotodani, Y., Ohno-Shosaku, T. & Kano, M. Presynaptic monoacylglycerol lipase activity determines basal endocannabinoid tone and terminates retrograde endocannabinoid signaling in the hippocampus. J. Neurosci. 27, 1211–1219 (2007).
Uchigashima, M. et al. Molecular and morphological configuration for 2-arachidonoylglycerol-mediated retrograde signaling at mossy cell–granule cell synapses in the dentate gyrus. J. Neurosci. 31, 7700–7714 (2011).
Gulyas, A. I. et al. Segregation of two endocannabinoid-hydrolyzing enzymes into pre- and postsynaptic compartments in the rat hippocampus, cerebellum and amygdala. Eur. J. Neurosci. 20, 441–458 (2004).
Ventura, R. & Harris, K. M. Three-dimensional relationships between hippocampal synapses and astrocytes. J. Neurosci. 19, 6897–6906 (1999).
Tanimura, A. et al. Synapse type-independent degradation of the endocannabinoid 2-arachidonoylglycerol after retrograde synaptic suppression. Proc. Natl Acad. Sci. USA 109, 12195–12200 (2012).
Brown, S. P., Brenowitz, S. D. & Regehr, W. G. Brief presynaptic bursts evoke synapse-specific retrograde inhibition mediated by endogenous cannabinoids. Nature Neurosci. 6, 1048–1057 (2003).
Losonczy, A., Biró, A. A. & Nusser, Z. Persistently active cannabinoid receptors mute a subpopulation of hippocampal interneurons. Proc. Natl Acad. Sci. USA 101, 1362–1367 (2004). This paper provides the first demonstration of CB1-dependent tonic inhibition of GABA release.
Neu, A., Földy, C. & Soltesz, I. Postsynaptic origin of CB1-dependent tonic inhibition of GABA release at cholecystokinin-positive basket cell to pyramidal cell synapses in the CA1 region of the rat hippocampus. J. Physiol. 578, 233–247 (2007).
Szabo, G. G. et al. Presynaptic calcium channel inhibition underlies CB1 cannabinoid receptor-mediated suppression of GABA release. J. Neurosci. 34, 7958–7963 (2014).
Ohno-Shosaku, T., Maejima, T. & Kano, M. Endogenous cannabinoids mediate retrograde signals from depolarized postsynaptic neurons to presynaptic terminals. Neuron 29, 729–738 (2001).
Wilson, R. I. & Nicoll, R. A. Endogenous cannabinoids mediate retrograde signalling at hippocampal synapses. Nature 410, 588–592 (2001).
Kreitzer, A. C. & Regehr, W. G. Retrograde inhibition of presynaptic calcium influx by endogenous cannabinoids at excitatory synapses onto Purkinje cells. Neuron 29, 717–727 (2001). References 46–48 demonstrate for the first time that eCBs mediate retrograde signalling for the transient suppression of synaptic transmission.
Maejima, T., Hashimoto, K., Yoshida, T., Aiba, A. & Kano, M. Presynaptic inhibition caused by retrograde signal from metabotropic glutamate to cannabinoid receptors. Neuron 31, 463–475 (2001).
Hashimotodani, Y. et al. Acute inhibition of diacylglycerol lipase blocks endocannabinoid-mediated retrograde signalling: evidence for on-demand biosynthesis of 2-arachidonoylglycerol. J. Physiol. 591, 4765–4776 (2013).
Pitler, T. A. & Alger, B. E. Depolarization-induced suppression of GABAergic inhibition in rat hippocampal pyramidal cells: G protein involvement in a presynaptic mechanism. Neuron 13, 1447–1455 (1994).
Hoffman, A. F. & Lupica, C. R. Mechanisms of cannabinoid inhibition of GABAA synaptic transmission in the hippocampus. J. Neurosci. 20, 2470–2479 (2000).
Pan, B. et al. Blockade of 2-arachidonoylglycerol hydrolysis by selective monoacylglycerol lipase inhibitor 4-nitrophenyl 4-(dibenzo[d][1,3]dioxol-5-yl(hydroxy)methyl)piperidine-1-carboxylate (JZL184) enhances retrograde endocannabinoid signaling. J. Pharmacol. Exp. Ther. 331, 591–597 (2009).
Földy, C., Neu, A., Jones, M. V. & Soltesz, I. Presynaptic, activity-dependent modulation of cannabinoid type 1 receptor-mediated inhibition of GABA release. J. Neurosci. 26, 1465–1469 (2006).
Maejima, T. et al. Synaptically driven endocannabinoid release requires Ca2+-assisted metabotropic glutamate receptor subtype 1 to phospholipase Cβ4 signaling cascade in the cerebellum. J. Neurosci. 25, 6826–6835 (2005).
Castillo, P. E. Presynaptic LTP and LTD of excitatory and inhibitory synapses. Cold Spring Harb. Perspect. Biol. 4, a005728 (2012).
Castillo, P. E., Younts, T. J., Chávez, A. E. & Hashimotodani, Y. Endocannabinoid signaling and synaptic function. Neuron 76, 70–81 (2012).
Buzsáki, G. Theta oscillations in the hippocampus. Neuron 33, 325–340 (2002).
Bartos, M., Vida, I. & Jonas, P. Synaptic mechanisms of synchronized gamma oscillations in inhibitory interneuron networks. Nature Rev. Neurosci. 8, 45–56 (2007).
Kucewicz, M. T., Tricklebank, M. D., Bogacz, R. & Jones, M. W. Dysfunctional prefrontal cortical network activity and interactions following cannabinoid receptor activation. J. Neurosci. 31, 15560–15568 (2011).
Hájos, N. et al. Cannabinoids inhibit hippocampal GABAergic transmission and network oscillations. Eur. J. Neurosci. 12, 3239–3249 (2000).
Robbe, D. et al. Cannabinoids reveal importance of spike timing coordination in hippocampal function. Nature Neurosci. 9, 1526–1533 (2006). This study shows that exocannabinoids disrupt the temporal coordination of neuronal assemblies.
Soltesz, I. & Staley, K. High times for memory: cannabis disrupts temporal coordination among hippocampal neurons. Nature Neurosci. 9, 1461–1463 (2006).
Holderith, N. et al. Cannabinoids attenuate hippocampal gamma oscillations by suppressing excitatory synaptic input onto CA3 pyramidal neurons and fast spiking basket cells. J. Physiol. 589, 4921–4934 (2011).
Sales-Carbonell, C. et al. Striatal GABAergic and cortical glutamatergic neurons mediate contrasting effects of cannabinoids on cortical network synchrony. Proc. Natl Acad. Sci. USA 110, 719–724 (2013).
Böcker, K. B. E. et al. Cannabinoid modulations of resting state EEG theta power and working memory are correlated in humans. J. Cogn. Neurosci. 22, 1906–1916 (2010).
Edwards, C. R., Skosnik, P. D., Steinmetz, A. B., O'Donnell, B. F. & Hetrick, W. P. Sensory gating impairments in heavy cannabis users are associated with altered neural oscillations. Behav. Neurosci. 123, 894–904 (2009); erratum 123, 1065 (2009).
Raver, S. M., Haughwout, S. P. & Keller, A. Adolescent cannabinoid exposure permanently suppresses cortical oscillations in adult mice. Neuropsychopharmacology 38, 2338–2347 (2013).
Lawrence, J. J. Cholinergic control of GABA release: emerging parallels between neocortex and hippocampus. Trends Neurosci. 31, 317–327 (2008).
Fisahn, A., Pike, F. G., Buhl, E. H. & Paulsen, O. Cholinergic induction of network oscillations at 40 Hz in the hippocampus in vitro. Nature 394, 186–189 (1998).
Nagode, D. A., Tang, A.-H., Karson, M. A., Klugmann, M. & Alger, B. E. Optogenetic release of ACh induces rhythmic bursts of perisomatic IPSCs in hippocampus. PLoS ONE 6, e27691 (2011).
Kim, J., Isokawa, M., Ledent, C. & Alger, B. E. Activation of muscarinic acetylcholine receptors enhances the release of endogenous cannabinoids in the hippocampus. J. Neurosci. 22, 10182–10191 (2002).
Ohno-Shosaku, T. et al. Postsynaptic M1 and M3 receptors are responsible for the muscarinic enhancement of retrograde endocannabinoid signalling in the hippocampus. Eur. J. Neurosci. 18, 109–116 (2003).
Gulyás, A. I. et al. Parvalbumin-containing fast-spiking basket cells generate the field potential oscillations induced by cholinergic receptor activation in the hippocampus. J. Neurosci. 30, 15134–15145 (2010).
Marsicano, G. & Lutz, B. Expression of the cannabinoid receptor CB1 in distinct neuronal subpopulations in the adult mouse forebrain. Eur. J. Neurosci. 11, 4213–4225 (1999).
Freund, T. F. & Katona, I. Perisomatic inhibition. Neuron 56, 33–42 (2007).
Gillies, M. J. et al. A model of atropine-resistant theta oscillations in rat hippocampal area CA1. J. Physiol. 543, 779–793 (2002).
Péterfi, Z. et al. Endocannabinoid-mediated long-term depression of afferent excitatory synapses in hippocampal pyramidal cells and GABAergic interneurons. J. Neurosci. 32, 14448–14463 (2012).
Puighermanal, E. et al. Cannabinoid modulation of hippocampal long-term memory is mediated by mTOR signaling. Nature Neurosci. 12, 1152–1158 (2009).
Albayram, O. et al. Role of CB1 cannabinoid receptors on GABAergic neurons in brain aging. Proc. Natl Acad. Sci. USA 108, 11256–11261 (2011).
Földy, C., Malenka, R. C. & Südhof, T. C. Autism-associated neuroligin-3 mutations commonly disrupt tonic endocannabinoid signaling. Neuron 78, 498–509 (2013). This study demonstrates that selective alterations occur in tonic, but not in phasic, eCB signalling at hippocampal synapses in mouse models of autism.
Lovinger, D. M. & Mathur, B. N. Endocannabinoids in striatal plasticity. Parkinsonism Relat. Disord. 18, S132–S134 (2012).
Iremonger, K. J., Cusulin, J. I. W. & Bains, J. S. Changing the tune: plasticity and adaptation of retrograde signals. Trends Neurosci. 36, 471–479 (2013).
Chen, K. et al. Long-term plasticity of endocannabinoid signaling induced by developmental febrile seizures. Neuron 39, 599–611 (2003). This paper provides the first evidence for persistent cell type-specific plasticity of the cannabinoid signalling system by seizures.
Chen, K. et al. Prevention of plasticity of endocannabinoid signaling inhibits persistent limbic hyperexcitability caused by developmental seizures. J. Neurosci. 27, 46–58 (2007).
Dvorzhak, A., Semtner, M., Faber, D. S. & Grantyn, R. Tonic mGluR5/CB1-dependent suppression of inhibition as a pathophysiological hallmark in the striatum of mice carrying a mutant form of huntingtin. J. Physiol. 591, 1145–1166 (2013).
Cepeda-Prado, E. et al. R6/2 Huntington's disease mice develop early and progressive abnormal brain metabolism and seizures. J. Neurosci. 32, 6456–6467 (2012).
Naydenov, A. V. et al. ABHD6 blockade exerts antiepileptic activity in PTZ-induced seizures and in spontaneous seizures in R6/2 mice. Neuron 83, 361–371 (2014).
Falenski, K. W. et al. Temporal characterization of changes in hippocampal cannabinoid CB1 receptor expression following pilocarpine-induced status epilepticus. Brain Res. 1262, 64–72 (2009).
Wallace, M. J., Blair, R. E., Falenski, K. W., Martin, B. R. & DeLorenzo, R. J. The endogenous cannabinoid system regulates seizure frequency and duration in a model of temporal lobe epilepsy. J. Pharmacol. Exp. Ther. 307, 129–137 (2003).
Falenski, K. W., Blair, R. E., Sim-Selley, L. J., Martin, B. R. & DeLorenzo, R. J. Status epilepticus causes a long-lasting redistribution of hippocampal cannabinoid type 1 receptor expression and function in the rat pilocarpine model of acquired epilepsy. Neuroscience 146, 1232–1244 (2007).
Bhaskaran, M. D. & Smith, B. N. Cannabinoid-mediated inhibition of recurrent excitatory circuitry in the dentate gyrus in a mouse model of temporal lobe epilepsy. PLoS ONE 5, e10683 (2010).
Ludányi, A. et al. Downregulation of the CB1 cannabinoid receptor and related molecular elements of the endocannabinoid system in epileptic human hippocampus. J. Neurosci. 28, 2976–2990 (2008). This paper describes the downregulation of components of the cannabinoid signalling system at precisely defined hippocampal synapses of humans with epilepsy.
Maglóczky, Z. et al. Dynamic changes of CB1-receptor expression in hippocampi of epileptic mice and humans. Epilepsia 51 (Suppl. 3), 115–120 (2010).
Monory, K. et al. The endocannabinoid system controls key epileptogenic circuits in the hippocampus. Neuron 51, 455–466 (2006).
Chang, B. S. & Lowenstein, D. H. Epilepsy. N. Engl. J. Med. 349, 1257–1266 (2003).
Goldberg, E. M. & Coulter, D. A. Mechanisms of epileptogenesis: a convergence on neural circuit dysfunction. Nature Rev. Neurosci. 14, 337–349 (2013).
Berkovic, S. F., Mulley, J. C., Scheffer, I. E. & Petrou, S. Human epilepsies: interaction of genetic and acquired factors. Trends Neurosci. 29, 391–397 (2006).
Hansen, H. H. et al. Anandamide, but not 2-arachidonoylglycerol, accumulates during in vivo neurodegeneration. J. Neurochem. 78, 1415–1427 (2001).
Panikashvili, D. et al. An endogenous cannabinoid (2-AG) is neuroprotective after brain injury. Nature 413, 527–531 (2001).
Marsicano, G. et al. CB1 cannabinoid receptors and on-demand defense against excitotoxicity. Science 302, 84–88 (2003).
Romigi, A. et al. Cerebrospinal fluid levels of the endocannabinoid anandamide are reduced in patients with untreated newly diagnosed temporal lobe epilepsy. Epilepsia 51, 768–772 (2010).
Wallace, M. J., Wiley, J. L., Martin, B. R. & DeLorenzo, R. J. Assessment of the role of CB1 receptors in cannabinoid anticonvulsant effects. Eur. J. Pharmacol. 428, 51–57 (2001).
Wallace, M. J., Martin, B. R. & DeLorenzo, R. J. Evidence for a physiological role of endocannabinoids in the modulation of seizure threshold and severity. Eur. J. Pharmacol. 452, 295–301 (2002).
Shafaroodi, H. et al. The interaction of cannabinoids and opioids on pentylenetetrazole-induced seizure threshold in mice. Neuropharmacology 47, 390–400 (2004).
Blair, R. E. et al. Activation of the cannabinoid type-1 receptor mediates the anticonvulsant properties of cannabinoids in the hippocampal neuronal culture models of acquired epilepsy and status epilepticus. J. Pharmacol. Exp. Ther. 317, 1072–1078 (2006).
Kozan, R., Ayyildiz, M. & Agar, E. The effects of intracerebroventricular AM-251, a CB1-receptor antagonist, and ACEA, a CB1-receptor agonist, on penicillin-induced epileptiform activity in rats. Epilepsia 50, 1760–1767 (2009).
Mason, R. & Cheer, J. F. Cannabinoid receptor activation reverses kainate-induced synchronized population burst fi ring in rat hippocampus. Front. Integr. Neurosci. 3, 13 (2009).
Carta, M., Fièvre, S., Gorlewicz, A. & Mulle, C. Kainate receptors in the hippocampus. Eur. J. Neurosci. 39, 1835–1844 (2014).
Lourenço, J. et al. Synaptic activation of kainate receptors gates presynaptic CB1 signaling at GABAergic synapses. Nature Neurosci. 13, 197–204 (2010).
Daw, M. I., Pelkey, K. A., Chittajallu, R. & McBain, C. J. Presynaptic kainate receptor activation preserves asynchronous GABA release despite the reduction in synchronous release from hippocampal cholecystokinin interneurons. J. Neurosci. 30, 11202–11209 (2010).
Burns, H. D. et al. [18F]MK-9470, a positron emission tomography (PET) tracer for in vivo human PET brain imaging of the cannabinoid-1 receptor. Proc. Natl Acad. Sci. USA 104, 9800–9805 (2007).
Goffin, K., Van Paesschen, W. & Van Laere, K. In vivo activation of endocannabinoid system in temporal lobe epilepsy with hippocampal sclerosis. Brain 134, 1033–1040 (2011). This paper uses brain imaging methods to demonstrate dynamic changes in CB1 availability in patients with temporal lobe epilepsy.
Perucca, P. & Gilliam, F. G. Adverse effects of antiepileptic drugs. Lancet Neurol. 11, 792–802 (2012).
Krook-Magnuson, E., Armstrong, C., Oijala, M. & Soltesz, I. On-demand optogenetic control of spontaneous seizures in temporal lobe epilepsy. Nature Commun. 4, 1376 (2013).
Schlosburg, J. E. et al. Chronic monoacylglycerol lipase blockade causes functional antagonism of the endocannabinoid system. Nature Neurosci. 13, 1113–1119 (2010).
Oviedo, A., Glowa, J. & Herkenham, M. Chronic cannabinoid administration alters cannabinoid receptor binding in rat brain: a quantitative autoradiographic study. Brain Res. 616, 293–302 (1993).
Guggenhuber, S., Monory, K., Lutz, B. & Klugmann, M. AAV vector-mediated overexpression of CB1 cannabinoid receptor in pyramidal neurons of the hippocampus protects against seizure-induced excitoxicity. PLoS ONE 5, e15707 (2010).
Stadnicki, S. W., Schaeppi, U., Rosenkrantz, H. & Braude, M. C. Δ9-tetrahydrocannabinol: subcortical spike bursts and motor manifestations in a Fischer rat treated orally for 109 days. Life Sci. 14, 463–472 (1974).
Martin, P. & Consroe, P. Cannabinoid induced behavioral convulsions in rabbits. Science 194, 965–967 (1976).
Gordon, E. & Devinsky, O. Alcohol and marijuana: effects on epilepsy and use by patients with epilepsy. Epilepsia 42, 1266–1272 (2001).
Kullmann, D. M., Schorge, S., Walker, M. C. & Wykes, R. C. Gene therapy in epilepsy — is it time for clinical trials? Nature Rev. Neurol. 10, 300–304 (2014).
Katona, I. et al. GABAergic interneurons are the targets of cannabinoid actions in the human hippocampus. Neuroscience 100, 797–804 (2000).
Eggan, S. M., Melchitzky, D. S., Sesack, S. R. & Fish, K. N. & Lewis, D. A. Relationship of cannabinoid CB1 receptor and cholecystokinin immunoreactivity in monkey dorsolateral prefrontal cortex. Neuroscience 169, 1651–1661 (2010).
Kovacs, F. E. et al. Exogenous and endogenous cannabinoids suppress inhibitory neurotransmission in the human neocortex. Neuropsychopharmacology 37, 1104–1114 (2012).
Maa, E. & Figi, P. The case for medical marijuana in epilepsy. Epilepsia 55, 783–786 (2014).
Cilio, M. R., Thiele, E. A. & Devinsky, O. The case for assessing cannabidiol in epilepsy. Epilepsia 55, 787–790 (2014).
Pitkänen, A. et al. Issues related to development of antiepileptogenic therapies. Epilepsia 54 (Suppl. 4), 35–43 (2013).
Echegoyen, J., Armstrong, C., Morgan, R. J. & Soltesz, I. Single application of a CB1 receptor antagonist rapidly following head injury prevents long-term hyperexcitability in a rat model. Epilepsy Res. 85, 123–127 (2009).
Dudek, F. E., Pouliot, W. A., Rossi, C. A. & Staley, K. J. The effect of the cannabinoid-receptor antagonist, SR141716, on the early stage of kainate-induced epileptogenesis in the adult rat. Epilepsia 51 (Suppl. 3), 126–130 (2010).
DeLong, M. R. & Wichmann, T. Circuits and circuit disorders of the basal ganglia. Arch. Neurol. 64, 20–24 (2007).
Mathur, B. N., Tanahira, C., Tamamaki, N. & Lovinger, D. M. Voltage drives diverse endocannabinoid signals to mediate striatal microcircuit-specific plasticity. Nature Neurosci. 16, 1275–1283 (2013).
Adermark, L. & Lovinger, D. M. Frequency-dependent inversion of net striatal output by endocannabinoid-dependent plasticity at different synaptic inputs. J. Neurosci. 29, 1375–1380 (2009).
Atwood, B. K., Kupferschmidt, D. A. & Lovinger, D. M. Opioids induce dissociable forms of long-term depression of excitatory inputs to the dorsal striatum. Nature Neurosci. 17, 540–548 (2014).
Fourgeaud, L. et al. A single in vivo exposure to cocaine abolishes endocannabinoid-mediated long-term depression in the nucleus accumbens. J. Neurosci. 24, 6939–6945 (2004).
Hoffman, A. F., Oz, M., Caulder, T. & Lupica, C. R. Functional tolerance and blockade of long-term depression at synapses in the nucleus accumbens after chronic cannabinoid exposure. J. Neurosci. 23, 4815–4820 (2003).
Mato, S. et al. A single in-vivo exposure to Δ9THC blocks endocannabinoid-mediated synaptic plasticity. Nature Neurosci. 7, 585–586 (2004).
Nazzaro, C. et al. SK channel modulation rescues striatal plasticity and control over habit in cannabinoid tolerance. Nature Neurosci. 15, 284–293 (2012).
DePoy, L. et al. Chronic alcohol produces neuroadaptations to prime dorsal striatal learning. Proc. Natl Acad. Sci. USA 110, 14783–14788 (2013).
Xia, J. X. et al. Alterations of rat corticostriatal synaptic plasticity after chronic ethanol exposure and withdrawal. Alcohol. Clin. Exp. Res. 30, 819–824 (2006).
Adermark, L., Jonsson, S., Ericson, M. & Söderpalm, B. Intermittent ethanol consumption depresses endocannabinoid-signaling in the dorsolateral striatum of rat. Neuropharmacology 61, 1160–1165 (2011).
Bagni, C. & Greenough, W. T. From mRNP trafficking to spine dysmorphogenesis: the roots of fragile X syndrome. Nature Rev. Neurosci. 6, 376–387 (2005).
Incorpora, G., Sorge, G., Sorge, A. & Pavone, L. Epilepsy in fragile X syndrome. Brain Dev. 24, 766–769 (2002).
Bhakar, A. L., Dölen, G. & Bear, M. F. The pathophysiology of fragile X (and what it teaches us about synapses). Annu. Rev. Neurosci. 35, 417–443 (2012).
Varma, N., Carlson, G. C., Ledent, C. & Alger, B. E. Metabotropic glutamate receptors drive the endocannabinoid system in hippocampus. J. Neurosci. 21, RC188 (2001).
Zhang, L. & Alger, B. E. Enhanced endocannabinoid signaling elevates neuronal excitability in fragile X syndrome. J. Neurosci. 30, 5724–5729 (2010).
Maccarrone, M. et al. Abnormal mGlu 5 receptor/endocannabinoid coupling in mice lacking FMRP and BC1 RNA. Neuropsychopharmacology 35, 1500–1509 (2010).
Jung, K.-M. et al. Uncoupling of the endocannabinoid signalling complex in a mouse model of fragile X syndrome. Nature Commun. 3, 1080 (2012).
Le Beau, F. E. N. & Alger, B. E. Transient suppression of GABAA-receptor-mediated IPSPs after epileptiform burst discharges in CA1 pyramidal cells. J. Neurophysiol. 79, 659–669 (1998).
Younts, T. J., Chevaleyre, V. & Castillo, P. E. CA1 pyramidal cell theta-burst firing triggers endocannabinoid-mediated long-term depression at both somatic and dendritic inhibitory synapses. J. Neurosci. 33, 13743–13757 (2013).
Harris, K. D., Csicsvary, J., Hirase, H., Dragoi, G. & Buzsaki, G. Organization of cell assemblies in the hippocampus. Nature 424, 552–556 (2003).
Deshpande, L. S. et al. Cannabinoid CB1 receptor antagonists cause status epilepticus-like activity in the hippocampal neuronal culture model of acquired epilepsy. Neurosci. Lett. 411, 11–16 (2007).
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.
The authors declare no competing financial interests.
Endogenous molecules, typically with marijuana-mimetic activity, that primarily act on type 1 and 2 cannabinoid receptors.
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.
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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