Endocannabinoids Generated by Ca2+ or by Metabotropic Glutamate Receptors Appear to Arise from Different Pools of Diacylglycerol Lipase

The identity and subcellular sources of endocannabinoids (eCBs) will shape their ability to affect synaptic transmission and, ultimately, behavior. Recent discoveries support the conclusion that 2-arachidonoyl glycerol, 2-AG, is the major signaling eCB, however, some important issues remain open. 2-AG can be synthesized by a mechanism that is strictly Ca2+-dependent, and another that is initiated by G-protein coupled receptors (GPCRs) and facilitated by Ca2+. An important question is whether or not the 2-AG in these cases is synthesized by the same pool of diacylglycerol lipase alpha (DAGLα). Using whole-cell voltage-clamp techniques in CA1 pyramidal cells in acute in vitro rat hippocampal slices, we investigated two mechanistically distinct eCB-mediated responses to address this issue. We now report that pharmacological inhibitors of DGLα have quantitatively different effects on eCB-mediated responses triggered by different stimuli, suggesting that functional, and perhaps physical, distinctions among pools of DAGLα exist

Developmental regulation of CB1-mediated spike-time dependent depression at immature mossy fiber-CA3 synapses

Early in postnatal life, mossy fibres (MF), the axons of granule cells in the dentate gyrus, release GABA which is depolarizing and excitatory. Synaptic currents undergo spike-time dependent long-term depression (STD-LTD) regardless of the temporal order of stimulation (pre versus post and viceversa). Here we show that at P3 but not at P21, STD-LTD, induced by negative pairing, is mediated by endocannabinoids mobilized from the postsynaptic cell during spiking-induced membrane depolarization. By diffusing backward, endocannabinoids activate cannabinoid type-1 (CB1) receptors probably expressed on MF. Thus, STD-LTD was prevented by CB1 receptor antagonists and was absent in CB1-KO mice. Consistent with these data, in situ hybridization experiments revealed detectable level of CB1 mRNA in the granule cell layer at P3 but not at P21. These results indicate that CB1 receptors are transiently expressed on immature MF terminals where they counteract the enhanced neuronal excitability induced by the excitatory action of GABA

Synaptic Neurotransmission Depression in Ventral Tegmental Dopamine Neurons and Cannabinoid-Associated Addictive Learning

Drug addiction is an association of compulsive drug use with long-term associative learning/memory. Multiple forms of learning/memory are primarily subserved by activity- or experience-dependent synaptic long-term potentiation (LTP) and long-term depression (LTD). Recent studies suggest LTP expression in locally activated glutamate synapses onto dopamine neurons (local Glu-DA synapses) of the midbrain ventral tegmental area (VTA) following a single or chronic exposure to many drugs of abuse, whereas a single exposure to cannabinoid did not significantly affect synaptic plasticity at these synapses. It is unknown whether chronic exposure of cannabis (marijuana or cannabinoids), the most commonly used illicit drug worldwide, induce LTP or LTD at these synapses. More importantly, whether such alterations in VTA synaptic plasticity causatively contribute to drug addictive behavior has not previously been addressed. Here we show in rats that chronic cannabinoid exposure activates VTA cannabinoid CB1 receptors to induce transient neurotransmission depression at VTA local Glu-DA synapses through activation of NMDA receptors and subsequent endocytosis of AMPA receptor GluR2 subunits. A GluR2-derived peptide blocks cannabinoid-induced VTA synaptic depression and conditioned place preference, i.e., learning to associate drug exposure with environmental cues. These data not only provide the first evidence, to our knowledge, that NMDA receptor-dependent synaptic depression at VTA dopamine circuitry requires GluR2 endocytosis, but also suggest an essential contribution of such synaptic depression to cannabinoid-associated addictive learning, in addition to pointing to novel pharmacological strategies for the treatment of cannabis addiction

A biophysical model of endocannabinoid-mediated short term depression in hippocampal inhibition

Memories are believed to be represented in the synaptic pathways of vastly interconnected networks of neurons. The plasticity of synapses, that is, their strengthening and weakening depending on neuronal activity, is believed to be the basis of learning and establishing memories. An increasing number of studies indicate that endocannabinoids have a widespread action on brain function through modulation of synap–tic transmission and plasticity. Recent experimental studies have characterised the role of endocannabinoids in mediating both short- and long-term synaptic plasticity in various brain regions including the hippocampus, a brain region strongly associated with cognitive functions, such as learning and memory. Here, we present a biophysically plausible model of cannabinoid retrograde signalling at the synaptic level and investigate how this signalling mediates depolarisation induced suppression of inhibition (DSI), a prominent form of shortterm synaptic depression in inhibitory transmission in hippocampus. The model successfully captures many of the key characteristics of DSI in the hippocampus, as observed experimentally, with a minimal yet sufficient mathematical description of the major signalling molecules and cascades involved. More specifically, this model serves as a framework to test hypotheses on the factors determining the variability of DSI and investigate under which conditions it can be evoked. The model reveals the frequency and duration bands in which the post-synaptic cell can be sufficiently stimulated to elicit DSI. Moreover, the model provides key insights on how the state of the inhibitory cell modulates DSI according to its firing rate and relative timing to the post-synaptic activation. Thus, it provides concrete suggestions to further investigate experimentally how DSI modulates and is modulated by neuronal activity in the brain. Importantly, this model serves as a stepping stone for future deciphering of the role of endocannabinoids in synaptic transmission as a feedback mechanism both at synaptic and network level

Astrocyte signaling controls spike timing-dependent depression at neocortical synapses

Endocannabinoid mediated spike timing-dependent depression (t-LTD) is crucially involved in the development of the sensory neocortex. t-LTD at excitatory synapses in the developing rat barrel cortex requires cannabinoid CB(1) receptor (CB(1)R) activation, as well as activation of NMDA receptors located on the presynaptic terminal, but the exact signaling cascade leading to t-LTD remains unclear. We found that astrocytes are critically involved in t-LTD. Astrocytes gradually increased their Ca(2+) signaling specifically during the induction of t-LTD in a CB(1)R-dependent manner. In this way, astrocytes might act as a memory buffer for previous coincident neuronal activity. Following activation, astrocytes released glutamate, which activated presynaptic NMDA receptors to induce t-LTD. Astrocyte stimulation coincident with afferent activity resulted in long-term depression, indicating that astrocyte activation is sufficient for the induction of synaptic depression. Taken together, our findings describe the retrograde signaling cascade underlying neocortical t-LTD. The critical involvement of astrocytes in this process highlights their importance for experience-dependent sensory remodeling

Insulin induces long-term depression of ventral tegmental area dopamine neurons via endocannabinoids.

The prevalence of obesity has markedly increased over the past few decades. Exploration of how hunger and satiety signals influence the reward system can help us understand non-homeostatic feeding. Insulin may act in the ventral tegmental area (VTA), a critical site for reward-seeking behavior, to suppress feeding. However, the neural mechanisms underlying insulin effects in the VTA remain unknown. We demonstrate that insulin, a circulating catabolic peptide that inhibits feeding, can induce long-term depression (LTD) of mouse excitatory synapses onto VTA dopamine neurons. This effect requires endocannabinoid-mediated presynaptic inhibition of glutamate release. Furthermore, after a sweetened high-fat meal, which elevates endogenous insulin, insulin-induced LTD is occluded. Finally, insulin in the VTA reduces food anticipatory behavior in mice and conditioned place preference for food in rats. Taken together, these results suggest that insulin in the VTA suppresses excitatory synaptic transmission and reduces anticipatory activity and preference for food-related cues