CB1 Receptor Signaling in the Brain: Extracting Specificity from Ubiquity

Abstract

Endocannabinoids (eCBs) are amongst the most ubiquitous signaling molecules in the nervous system. Over the past few decades, observations based on a large volume of work, first examining the pharmacological effects of exogenous cannabinoids, and then the physiological functions of eCBs, have directly challenged long-held and dogmatic views about communication, plasticity and behavior in the central nervous system (CNS). The eCBs and their cognate cannabinoid receptors exhibit a number of unique properties that distinguish them from the widely studied classical amino-acid transmitters, neuropeptides, and catecholamines. Although we now have a loose set of mechanistic rules based on experimental findings, new studies continue to reveal that our understanding of the eCB system (ECS) is continuously evolving and challenging long-held conventions. Here we will briefly summarize findings on the current canonical view of the 'ECS' and will address novel aspects that reveal how a nearly ubiquitous system can determine highly specific functions in the brain. In particular, we will focus on findings that push for an expansion of our ideas around long-held beliefs about eCB signaling that, while clearly true, may be contributing to an oversimplified perspective on how cannabinoid signaling at the microscopic level impacts behavior at the macroscopic level.

Figure 1

Schematic view of potential localizations of CB₁ receptors at the synapse. CB₁ receptors are present at both presynaptic terminals and postsynaptic compartments of neurons and on astrocytes, exerting different impacts at the tripartite synapse. Whereas the presynaptic plasma membrane localization is long recognized, new evidence points to the presence of CB₁ at mitochondrial membranes of both presynaptic and somatodendritic compartments of neurons, although their specific functions are still to be fully determined. The presence of CB₁ at postsynaptic plasma membranes is possible, but no direct anatomical evidence for this exists so far. Endosomal CB₁ expression has been also proposed by different studies. CB₁ (and possibly mtCB₁) receptors are present in astrocytes, where they control astroglial synaptic functions. For additional information see the main text.

Figure 2

Schematic view of the mtCB₁-dependent signaling pathway. CB₁ receptors are present in brain mitochondria likely in the external membrane where they regulate the respiratory chain and ultimately the mitochondrial functions (eg, ATP production). On the right, we represented the signaling pathway downstream mtCB₁ receptors. It has been described that mtCB₁ receptors mediate its effects involving intra-mitochondrial G_i/o protein signaling, mitochondrial cAMP synthesis that is catalyzed by a soluble form of adenylyl cyclase (sAC), and the decrease of intra-mitochondrial PKA activity that also reduced phosphorylation of specific subunits of complex I (eg, NDUFS2). All these events can impair the respiratory chain decreasing mitochondrial respiration, likely affecting other mitochondria functions. For additional information refer to the main text.

Figure 3

CB₁-mediated effects, release probability, and presynaptic activity on postsynaptic firing. (a) Schematic depiction of a GABA synapse (blue) that has a high initial release probability. With rapid, repeated activation of the presynaptic neuron, GABA release decreases. (b) Blue traces show the spike patterns in the presynaptic neuron and the putative synaptic response immediately below in a condition when CB₁ receptors are not recruited. In orange, the activity of postsynaptic neuron and the effect of the inhibitory event. Note that a single presynaptic action potential is sufficient to elicit a pause in firing of the postsynaptic neuron. A burst of presynaptic action potentials elicits a pause that is marginally longer, but rapid synaptic depression allows postsynaptic firing to resume quickly. (c) When CB₁ receptors are recruited, a single action potential evokes no release and consequently, postsynaptic firing is unaffected. A burst of presynaptic action potentials, however, results in synaptic facilitation and a prolonged pause in postsynaptic firing. (d) Schematic depiction of a GABA synapse (green) that has a low initial release probability. With rapid, repeated activation of the presynaptic neuron, GABA release increases. (e) Green traces show the spike patterns in the presynaptic neuron and the putative synaptic response immediately below in a condition when CB₁ receptors are not recruited. In orange, the activity of postsynaptic neuron and the effect of the inhibitory event. Note that a single presynaptic action potential has no effect on firing of the postsynaptic neuron. A burst of presynaptic action potentials results in synaptic currents that facilitate and cause a delayed pause in firing of the postsynaptic neuron. (f) When CB₁ receptors are recruited, a single action potential still evokes no release and again, postsynaptic firing is unaffected. A burst of presynaptic action potentials, however, results in very profound synaptic facilitation and a prolonged pause in postsynaptic firing.