An ‘exciting’ spin on cannabinoid signalling

It has long been appreciated that cannabinoid administration alters cognitive functioning, including learning and memory. These effects are thought to arise, at least in part, from alterations in synchronous activity in the cortex and hippocampus. The synaptic mechanisms underlying these effects, however, have not been clearly delineated. In recent years, the endogenous cannabinoid system has emerged as a powerful mechanism for regulating the release of neurotransmitter from presynaptic terminals (reviewed in Kano et al. 2009). The type 1 cannabinoid (CB1) receptor, which may be the most highly expressed G protein-coupled receptor in the brain, is found throughout the neuraxis, with particularly high levels in the hippocampus, neocortex, cerebellum and basal ganglia. At the subcellular level, the CB1 receptor is predominantly found in presynaptic terminals. Initial localization studies focused on the high levels of CB1 expression in a subset of GABAergic interneurons that co-express the peptide cholecystokinin (CCK). Recent studies have revealed that CB1 receptors are also expressed widely in glutamatergic terminals, as well as in some cholinergic, noradrenergic, and serotonergic terminals. In fact, CB1 receptor-mediated regulation of glutamate release, rather than GABA release, plays a central role in mediating the classic tetrad of behavioural and physiological responses to systemic cannabinoid administration (Monory et al. 2007). Endocannabinoid signalling is involved in a diverse range of physiological as well as pathophysiological processes, and identifying the underlying synaptic mechanisms and the relevant neuronal populations is important for the development of novel therapeutic strategies targeting the endocannabinoid system. In a recent issue of The Journal of Physiology, Holderith et al. (2011) explore the mechanisms underlying cannabinoid suppression of hippocampal gamma oscillations using in vitro brain slices. Cannabinoids are known to disrupt synchronous neuronal activity in several frequency bands, both in vitro and in vivo. Hippocampal theta (4–12 Hz), gamma (30–80 Hz), and sharp-wave ripple (100–200 Hz) oscillations have all been shown to be disrupted by cannabinoids (Robbe et al. 2006). The synchronous activity of neuronal populations at these frequencies is critically involved in various forms of hippocampal-dependent learning and memory. Specifically, theta and gamma oscillations are thought to play a role in the encoding of information (cortical to hippocampal transmission) and sharp-wave ripples are involved in memory consolidation and information transfer from hippocampal to cortical regions. Gamma oscillations are also disrupted in disorders such as Alzheimer's disease and schizophrenia. Understanding the synaptic mechanisms that regulate these oscillations could therefore shed light on the role of rhythmic processes in physiological and pathophysiological conditions. The synchronized spiking of large groups of pyramidal neurons that gives rise to hippocampal oscillations is controlled by the rhythmic activity of distinct sets of hippocampal interneurons, especially basket cells that provide perisomatic inhibition of principal neurons. For example, a subset of CCK-expressing regular-spiking basket cells are thought to contribute to the regulation of theta rhythms, and these cells express the CB1 receptor in their axon terminals. Fast-spiking basket cells that contain parvalbumin are involved in the generation of theta as well as gamma oscillations, and these cells lack CB1 receptor expression. Nonetheless, theta and gamma oscillations are sensitive to cannabinoids, although the underlying cellular/synaptic mechanisms are not well understood. In their paper, Holderith et al. focus on the cannabinoid-mediated dampening of gamma oscillations in the CA3 region of the hippocampus induced by the muscarinic receptor agonist carbachol (CCh). They found that the effect of cannabinoid agonists on the peak power of the CCh-induced gamma rhythm arises not from a reduction of inhibitory input onto CA3 pyramidal neurons, but instead via reduced excitatory input onto both fast-spiking basket cells and CA3 pyramidal neurons. This reduction in excitatory transmission is accompanied by reduced and desynchronized neuronal firing, resulting in smaller field potentials. Cannabinoids dampened sharp-wave ripple activity as well (Holderith et al. 2011), an effect that has also been attributed to suppression of glutamate release (Maier et al. 2011). Thus, cannabinoid regulation of rhythmic oscillations can occur via CB1 receptor-mediated suppression of glutamate release onto principal neurons and fast-spiking interneurons, in addition to suppression of GABA release from CCK/CB1-expressing basket cells. Taken together, these results deepen our understanding of the functional consequences of cannabinoid receptor activation on network activity and shed light on underlying synaptic mechanisms. Modulation of glutamatergic nerve terminals also mediates the neuroprotective and anticonvulsant effects of cannabinoids; however, cannabinoid inhibition of GABA release can be proconvulsant under some conditions. Thus, selective cannabinoid-induced modulation of excitatory terminals could have great therapeutic potential. Future work could extend these results by exploring the interplay between different classes of neuromodulators that regulate oscillations via distinct mechanisms (e.g. opioids, histamine). Another important future direction will be to explore the functional role of endogenous CB1 receptor ligands, which, acting as retrograde messengers in a synapse-specific manner, may alter the synchronized activity of spatially-restricted subsets of neuronal assemblies.