Control of synaptic function by endocannabinoid-mediated retrograde signaling

Abstract

Since the first reports in 2001, great advances have been made towards the understanding of endocannabinoid-mediated synaptic modulation. Electrophysiological studies have revealed that one of the two major endocannabinoids, 2-arachidonoylglycerol (2-AG), is produced from membrane lipids upon postsynaptic Ca(2+) elevation and/or activation of Gq/11-coupled receptors, and released from postsynaptic neurons. The released 2-AG then acts retrogradely onto presynaptic cannabinoid CB1 receptors and induces suppression of neurotransmitter release either transiently or persistently. These forms of 2-AG-mediated retrograde synaptic modulation are functional throughout the brain. The other major endocannabinoid, anandamide, mediates a certain form of endocannabinoid-mediated long-term depression (LTD). Anandamide also functions as an agonist for transient receptor potential vanilloid receptor type 1 (TRPV1) and mediates endocannabinoid-independent and TRPV1-dependent forms of LTD. It has also been demonstrated that the endocannabinoid system itself is plastic, which can be either up- or down-regulated by experimental or environmental conditions. In this review, I will make an overview of the mechanisms underlying endocannabinoid-mediated synaptic modulation.

Figure 1.

Key features of 2-AG signaling. PLC hydrolyzes arachidonic acid-containing membrane phospholipid such as phosphatidylinositol (PI) and generates diacylglycerol (DG), which is then converted to 2-AG by DGL. The 2-AG released from the postsynaptic neuron enters into the presynaptic membrane, activates CB₁R and is degraded by presynaptic MGL. In the postsynaptic neuron, 2-AG is degraded by ABHD6 or oxigenated by COX-2. Activation of presynaptic CB₁R causes suppression of neurotransmitter release through inhibition of Ca²⁺ channels or some other mechanisms. (Reproduced from Ohno-Shosaku et al., 2012¹⁵⁾).

Figure 2.

Representative cases for Ca²⁺-driven endocannabinoid release (CaER) and Ca²⁺-assisted Receptor-driven endocannabinoid release (RER). A. Representative data showing DSI, a form of CaER, in a neuron pair from a hippocampal culture. The presynaptic neuron was stimulated and inhibitory postsynaptic currents (IPSCs) were recorded from the postsynaptic neuron. Amplitudes of IPSCs were plotted as a function of time (upper panel) and IPSCs recorded at the indicated time points were shown in the lower panels. Depolarizing pulses (to 0 mV for 5 sec) to the postsynaptic neuron (downward arrow) induced a transient suppression of IPSCs (DSI). After treatment of the CB₁ antagonist AM281, DSI was abolished. (Reproduced from Hashimotodani et al., 2007²⁸⁾). B. Representative data showing Ca²⁺-assisted RER in a neuron pair from a hippocampal culture. Time course of IPSC amplitude (left panel) and IPSC recorded at the indicated time points (right panels) were shown. Application of a low concentration of the muscarinic agonist oxotremorine-M (oxo-M, 0.3 µM) or a weak depolarizing pulse (downward arrow) caused no detectable suppression of IPSCs when applied alone. However, combined application of these two caused a robust suppression of IPSCs. (Reproduced from Hashimotodani et al., 2005⁶⁰⁾).

Figure 3.

Molecular mechanisms of eCB-STD. When a large Ca²⁺ elevation is caused by activation of voltage-gated Ca²⁺ channels or NMDARs, 2-AG is generated in a DGLα-dependent manner (a, CaER). A key enzyme of this pathway, which is expected to be activated by Ca²⁺ elevation and produce diacylglycerol, is not identified. When PLCβ is stimulated by activation of G_q/11-coupled receptors, diacylglycerol is generated and converted to 2-AG by DGLα (b, RER). When subthreshold activation of G_q/11-coupled receptors is combined with a small Ca²⁺ elevation, 2-AG is produced through PLCβ-dependent pathway because the receptor-driven PLCβ stimulation is Ca²⁺-dependent (c, Ca²⁺-assisted RER). 2-AG is released from postsynaptic neurons, activates presynaptic CB₁R, and induces transient suppression of transmitter release. (Reproduced with modification from Ohno-Shosaku et al., 2012¹⁵⁾).

Figure 4.

Molecular mechanisms of eCB-LTD. Excitatory synaptic inputs activate group I mGluR, which facilitates 2-AG synthesis through PLCβ-DGLα pathway. This mGluR-driven 2-AG synthesis is enhanced by concomitant Ca²⁺ elevation, which is not necessary for eCB-LTD induction at some synapses. Activation of presynaptic CB₁R by 2-AG inhibits adenylyl cyclase (AC), decreases cAMP levels and reduces PKA activity. Presynaptic activity causes Ca²⁺ elevation, which activates a phosphatase, calcineurin (CaN). In concert with reduced PKA activity, calcineurin facilitates dephosphorylation of target proteins (X), and induces persistent suppression of transmitter release through RIM1α-dependent and/or -independent processes. (Reproduced from Ohno-Shosaku et al., 2012¹⁵⁾).