Recent studies have clarified that endogenous cannabinoids are released from depolarized postsynaptic neurons in a calcium-dependent manner and act retrogradely onto presynaptic cannabinoid receptors to suppress neurotransmitter release.
Marijuana exerts variable behavioral effects through the interaction of its active component Δ9-tetrahydrocannabinol with specific cannabinoid receptors. They constitute a family of G protein-coupled seven-transmembrane-domain receptors and consist of type 1 (CB1) and type 2 (CB2) receptors.1,2,3,4 While the CB2 is expressed mostly in the immune system, the CB1 is rich in various regions of the brain.5,6 Anandamide and sn-2-arachidonylglycerol (2-AG)1,2,3,4 have so far been identified as putative endogenous ligands for the CB1. These endogenous cannabinoids (endocannabinoids) are reported to be produced and released from central neurons in a manner dependent on neural activity and intracellular Ca2+.1,2,3,4 Activation of the CB1 causes suppression of synaptic transmission in various regions of the CNS.1,2
The synapse is a main target of various neuromodulators in the CNS. Several forms of activity-dependent synaptic modulation are found, and some of them involve retrograde messengers that transmit signals from postsynaptic neurons to presynaptic terminals.7 Recent studies have revealed that endocannabinoids play a key role as a retrograde messenger in activity-dependent modulations at both excitatory and inhibitory synapses.8,9,10 In the following sections, we introduce these studies and propose a possible scheme how endocannabinoids modulate synaptic transmission.
In the hippocampus11,12 and the cerebellum,13 action potential firing or depolarization of the postsynaptic neuron induces a transient suppression of inhibitory synaptic inputs to the depolarized neuron. This phenomenon, termed DSI (depolarization-induced suppression of inhibition), is initiated postsynaptically by an elevation of cytoplasmic Ca2+ concentration ([Ca2+]i) and is expressed presynaptically as a suppression of the transmitter release.11,12,13 Therefore, some retrograde signal must exist from the depolarized postsynaptic neurons to the presynaptic terminals.
The possibility that endocannabinoids may mediate the retrograde signaling of DSI has been evaluated recently, by using cultured neurons9 and acute slices10 from the hippocampus. In cultures, DSI occurs at about half of the inhibitory synapses.11 At all the DSI-positive synapses, the synthetic cannabinoid agonist WIN55,212-2 suppresses the release of the inhibitory neurotransmitter GABA from presynaptic terminals.9 In contrast, WIN55,212-2 is ineffective at most of the synapses that do not exhibit DSI.9 Most importantly, DSI is completely eliminated by synthetic cannabinoid antagonists, AM 281 and SR141716A.9 In hippocampal slices, Wilson and Nicoll present essentially the same results as those in cultures.10 In addition, they show that DSI is not inhibited by postsynaptically-applied botulinum toxin, making vesicular release from the postsynaptic cell highly improbable.10 They also demonstrate that liberation of Ca2+ alone via flash photolysis of caged Ca2+ is sufficient to induce DSI.10 All these data are consistent with the notion that endocannabinoids function as a retrograde messenger for DSI.
Because the CB1 receptor is rich in not only inhibitory but also excitatory presynaptic fibers,5 it is highly likely that endocannabinoids released from postsynaptic neurons can reduce the release of excitatory transmitter. Kreitzer and Regehr have demonstrated recently that brief depolarization of cerebellar Purkinje cells induces a transient suppression of excitatory synaptic transmission at both climbing fiber and parallel fiber synapses.8 This depolarization-induced suppression of excitation (DSE) lasts for tens of seconds and is blocked by the postsynaptic injection of a fast Ca2+ chelator BAPTA.8 DSE is completely eliminated by the cannabinoid receptor antagonist.8 All these properties are quite similar to those of DSI, and indicate that endocannabinoids are released from depolarized Purkinje cells, and suppress the glutamate release from presynaptic terminals through the activation of the presynaptic CB1. In addition, Kreitzer and Regehr demonstrate that action potential-evoked rise of [Ca2+]i in climbing fiber terminals is decreased during DSE.8 This result strongly suggests that DSE results from the decreased Ca2+ influx to presynaptic terminals.
DSI and DSE appear to have mechanisms in common (Figure 1). Postsynaptic depolarization triggers Ca2+ influx through voltage-gated Ca2+ channels, and causes a transient increase in [Ca2+]i. The [Ca2+]i increase stimulates the biosynthesis of endocannabinoids and causes their release from the depolarized neuron. The released endocannabinoids bind to the CB1 on the inhibitory or excitatory presynaptic terminals contacting onto the depolarized neuron, and suppress the release of GABA or glutamate, presumably by inhibiting voltage-gated Ca2+ channels.14
Functions of presynaptic terminals are thought to be controlled by neurotransmitters through autocrine mechanisms. For example, GABA released from GABAergic presynaptic terminals will suppress further GABA release via activation of GABAB autoreceptors on the terminals. Similarly, the release of glutamate is thought to be controlled by metabotropic glutamate receptors (mGluRs) on glutamatergic presynaptic terminals. In addition to these ‘homosynaptic’ modulations through presynaptic autoreceptors, transmission can be controlled heterosynaptically. The GABA release is suppressed by glutamate via mGluRs, while the glutamate release is suppressed by GABA via GABAB receptors. These types of modulation are dependent on the activity of presynaptic terminals.
In contrast, the endocannabinoid-mediated modulation described here is dependent on the postsynaptic activity, and thus it is classified as a novel form of activity-dependent synaptic modulation. Endocannabinoid release is triggered by an elevation of [Ca2+]i in postsynaptic neurons. The elevation of [Ca2+]i is caused by the activation of postsynaptic receptors and channels, and reflects the activity of postsynaptic neurons. Presynaptic terminals can sense the postsynaptic activity by detecting released endocannabinoids from postsynaptic neurons with the CB1. Because the CB1 is abundantly expressed in various regions of CNS,5,6 it is highly likely that the retrograde modulation mediated by endocannabinoids is a general and important mechanism by which the postsynaptic activity can influence the presynaptic function.
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This work was supported in part by Grants-in-Aid for Scientific Research (to TO-S and MK) and Special Coordination Funds for Promoting Science and Technology (to MK) from the Ministry of Education, Science, Sports, Culture and Technology of Japan.
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Kano, M., Ohno-Shosaku, T. & Maejima, T. Retrograde signaling at central synapses via endogenous cannabinoids. Mol Psychiatry 7, 234–235 (2002). https://doi.org/10.1038/sj.mp.4000999
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