Cannabinoid receptor activation modifies NMDA receptor mediated release of intracellular calcium: Implications for endocannabinoid control of hippocampal neural … (original) (raw)
Related papers
Ryanodine Receptor Regulates Endogenous Cannabinoid Mobilization in the Hippocampus
Journal of Neurophysiology, 2006
Endogenous cannabinoids (eCBs) are produced and mobilized in a cytosolic calcium ([Ca2+]i)–dependent manner, and they regulate excitatory and inhibitory neurotransmitter release by acting as retrograde messengers. An indirect but real-time bioassay for this process on GABAergic transmission is DSI (depolarization-induced suppression of inhibition). The magnitude of DSI correlates linearly with depolarization-induced increase of [Ca2+]ithat is thought to be initiated by Ca2+influx through voltage-gated Ca2+channels. However, the identity of Ca2+sources involved in eCB mobilization in DSI remains undetermined. Here we show that, in CA1 pyramidal cells, DSI-inducing depolarizing voltage steps caused Ca2+-induced Ca2+release (CICR) by activating the ryanodine receptor (RyR) Ca2+-release channel. CICR was reduced, and the remaining increase in [Ca2+]iwas less effective in generating DSI, when the RyR antagonists, ryanodine or ruthenium red, were applied intracellularly, or the Ca2+stores...
British Journal of Pharmacology, 2009
Background and purpose: Inhibitory CB 1 cannabinoid receptors and excitatory TRPV 1 vanilloid receptors are abundant in the hippocampus. We tested if two known hybrid endocannabinoid/endovanilloid substances, N-arachidonoyl-dopamine (NADA) and anandamide (AEA), presynapticaly increased or decreased intracellular calcium level ([Ca 2 þ ] i ) and GABA and glutamate release in the hippocampus. Experimental approach: Resting and K þ -evoked levels of [Ca 2 þ ] i and the release of [ 3 H]GABA and [ 3 H]glutamate were measured in rat hippocampal nerve terminals. Key results: NADA and AEA per se triggered a rise of [Ca 2 þ ] i and the release of both transmitters in a concentration-and external Ca 2 þ -dependent fashion, but independently of TRPV 1 , CB 1 , CB 2 , or dopamine receptors, arachidonate-regulated Ca 2 þ -currents, intracellular Ca 2 þ stores, and fatty acid metabolism. AEA was recently reported to block TASK-3 potassium channels thereby depolarizing membranes. Common inhibitors of TASK-3, Zn 2 þ , Ruthenium Red, and low pH mimicked the excitatory effects of AEA and NADA, suggesting that their effects on [Ca 2 þ ] i and transmitter levels may be attributable to membrane depolarization upon TASK-3 blockade. The K þ -evoked Ca 2 þ entry and Ca 2 þ -dependent transmitter release were inhibited by nanomolar concentrations of the CB 1 receptor agonist WIN55212-2; this action was sensitive to the selective CB 1 receptor antagonist AM251. However, in the low micromolar range, WIN55212-2, NADA and AEA inhibited the K þ -evoked Ca 2 þ entry and transmitter release independently of CB 1 receptors, possibly through direct Ca 2 þ channel blockade. Conclusions and implications: We report here for hybrid endocannabinoid/endovanilloid ligands novel dual functions which were qualitatively similar to activation of CB 1 or TRPV 1 receptors, but were mediated through interactions with different targets.
Mechanisms of endocannabinoid mobilization in hippocampus
2005
Endocannabinoids (eCBs) act as retrograde messengers at inhibitory synapses of the hippocampal CA1 region. Current models place eCB synthesis in the postsynaptic pyramidal cell and the site of eCB action at cannabinoid (CB1) receptors located on presynaptic interneuron terminals. Four responses at the CA1-interneuron synapse are attributed to eCBs; depolarization-induced suppression of inhibition (DSI), G-protein-coupled receptor mediated enhancement of DSI (∆DSI), persistent suppression of eIPSCs, and finally, mGluR-dependent long-term depression (iLTD). It has been proposed that all are mediated by the eCB, 2-arachidonoyl glycerol (2-AG), yet there is evidence that DSI does not arise from the same underlying biochemical processes as the other responses. In view of the increasing importance of eCB effects in the brain, it will be essential to understand the mechanisms by which eCB effects are produced. Our results reveal new differences in the biochemical pathways by which the eCB-...
Brain Research Bulletin, 2017
Long-term potentiation (LTP) of synaptic responses is a widely researched model of synaptic plasticity that occurs during learning and memory. The cannabinoid system is an endogenous system that modulate this kind of synaptic plasticity. In addition, voltage dependent calcium channels is essential for induction of LTP at some synapses in the hippocampus. However, there is currently debate over the interaction between L-type calcium channels and cannabinoid system on the synaptic plasticity. In this study, we examined the effects of an acute administration of the cannabinoid antagonist AM251 following a chronic administration of the Ca 2+ channel blocker verapamil on LTP induction in the hippocampal dentate gyrus(DG) of rats. Male Wistar rats were administered verapamil(10,25,50 mg/kg) or saline intraperitoneally(IP) daily for 13 days(n = 10/group). After this treatment period, animals were anesthetized with an IP injection of urethane; the recording and stimulating electrodes were positioned in the DG and the perforant pathway. After obtaining a steady state baseline response, a single IP injection of saline or AM251(1 or 5 mg/kg) was administered. LTP was induced by highfrequency stimulation(HFS). The population spike(PS) amplitude and the slope of excitatory postsynaptic potentials(EPSP) were compared between the experimental groups. The acute administration of the CB1 antagonist AM251 increased LTP induction. The EPSP slopes and PS amplitude in the verapamil and AM251 groups differed after HFS, such that AM251 increased LTP, whereas verapamil decreased LTP induction. These findings suggest that there are functional interactions between the L-type calcium channels and cannabinoid system in this model of synaptic plasticity in the hippocampus.
Cannabinoid CB1 Receptor Calibrates Excitatory Synaptic Balance in the Mouse Hippocampus
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2015
The endocannabinoid system negatively regulates the release of various neurotransmitters in an activity-dependent manner, thereby influencing the excitability of neuronal circuits. In the hippocampus, cannabinoid type 1 (CB1) receptor is present on both GABAergic and glutamatergic axon terminals. CB1 receptor-deficient mice were previously shown to have increased hippocampal long-term potentiation (LTP). In this study, we have investigated the consequences of cell-type-specific deletion of the CB1 receptor on the induction of hippocampal LTP and on CA1 pyramidal cell morphology. Deletion of CB1 receptor in GABAergic neurons in GABA-CB1-KO mice leads to a significantly decreased hippocampal LTP compared with WT controls. Concomitantly, CA1 pyramidal neurons have a significantly reduced dendritic branching both on the apical and on the basal dendrites. Moreover, the average spine density on the apical dendrites of CA1 pyramidal neurons is significantly diminished. In contrast, in mice...
Neuroscience, 2016
Recent research points to diversification in the local neuronal circuitry between dorsal (DH) and ventral (VH) hippocampus that may be involved in the large-scale functional segregation along the long axis of the hippocampus. Here, using CA1 field recordings from hippocampal slices, we show that activation of N-methyl-D-aspartate receptors (NMDARs) reduced excitatory transmission more in VH than in DH, with an adenosine A1 receptor-independent mechanism, and reduced inhibition and enhanced postsynaptic excitability only in DH. Strikingly, co-activation of metabotropic glutamate receptor-5 (mGluR5) with NMDAR, with CHPG and NMDA respectively, strongly potentiated the effects of NMDAR in DH but had not any potentiating effect in VH. Furthermore, the synergistic actions in DH were occluded by blockade of adenosine A 2A receptors (A 2A Rs) by their antagonist ZM 241385 demonstrating a tonic action of these receptors in DH. Exogenous activation of A 2A Rs by 4-[2-[[6-amino-9-(N-ethyl-b-D-ribofuranuronamidosyl)-9Hpurin-2-yl]amino]ethyl]benzenepropanoic acid hydrochloride (CGS 21680) did not change the effects of mGluR5-NMDAR co-activation in either hippocampal pole. Importantly, blockade of cannabinoid CB1 receptors by their antagonist 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-4-morpholinyl-1H-pyrazole-3-carboxamide (AM 281) restricted the synergistic actions of mGluR5-NMDARs on excitatory synaptic transmission and postsynaptic excitability and abolished their potentiating effect on inhibition. Furthermore, AM 281 increased the excitatory transmission only in DH indicating that cannabinoid 1 receptors (CB 1 Rs) were tonically active in DH but not VH. Removing the magnesium ions from the perfusion medium neither stimulated the interaction between mGluR5 and NMDAR in VH nor augmented the synergy of the two receptors in DH. These findings show that the NMDAR-dependent modulation of fundamental parameters of the local neuronal network, by mGluR, A 2A R and CB 1 R, markedly differs between DH and VH. We propose that the higher modulatory role of A2AR and mGluR5, in combination with the role of CB 1 Rs, provide DH with higher functional flexibility of its NMDARs, compared with VH.
The CB1 cannabinoid receptor mediates glutamatergic synaptic suppression in the hippocampus
Neuroscience, 2006
Cannabinoids have profound effects on synaptic function and behavior. Of the two cloned cannabinoid receptors, cannabinoid receptor 1 (CB1) is widely distributed in the CNS and accounts for most of the neurological effects of cannabinoids, while cannabinoid receptor 2 (CB2) expression in the CNS is very limited. The presence of additional receptors [i.e. cannabinoid receptor 3 (CB3)] is suggested by growing evidence of cannabinoid effects that are not mediated by CB1 or CB2. The most direct functional evidence for a CB3 comes from a study in hippocampus where deletion of CB1 was shown to have no effect on cannabinoid-mediated suppression of the excitatory synapse between Schaffer collateral/commissural fibers and CA1 pyramidal cells [Novel cannabinoid-sensitive receptor mediates inhibition of glutamatergic synaptic transmission in the hippocampus. Neuroscience 106:1-4]. In contrast, we report here that in extracellular field recordings, the cannabinoid agonist WIN 55,212-2 (5 microM) had no effect on Schaffer collateral/commissural fiber-CA1 pyramidal cell (Sch-CA1) synaptic transmission in slices from two independently made cannabinoid receptor 1-/- lines [Zimmer et al 1999 and Ledent et al 1999] while strongly suppressing Sch-CA1 synaptic transmission in CB1+/+ mice of the background strains. Also, we observed robust cannabinoid-mediated suppression of the Sch-CA1 synapse in pure C57BL/6 mice, contradicting a recent report that cannabinoid suppression of this synapse is absent in this strain [Hoffman AF, Macgill AM, Smith D, Oz M, Lupica CR (2005) Species and strain differences in the expression of a novel glutamate-modulating cannabinoid receptor in the rodent hippocampus. Eur J Neurosci 22:2387-2391]. Our results strongly suggest that cannabinoid-induced suppression of the Sch-CA1 synapse is mediated by CB1. Non-canonical cannabinoid receptors do not seem to play a major role in inhibiting transmitter release at this synapse.
Journal of Neurophysiology, 2004
GABAergic synapses that is initiated by the calcium-and depolarization-dependent release of endocannabinoids from postsynaptic neurons. In the neocortex, pyramidal neurons (PNs) appear to use DSI as a mechanism for regulating somatic inhibition from a subpopulation of GABAergic inputs that express the type 1 cannabinoid receptor. Although postsynaptic control of afferent inhibition may directly influence the integrative properties of neocortical PNs, little is known regarding the patterns of activity that evoke endocannabinoid release and the impact such disinhibition may have on the excitability of PNs. Here we provide the first systematic survey of AP-induced DSI in the neocortex. The magnitude and time course of DSI was directly related to the number and frequency of postsynaptic APs and was enhanced in the presence of the cholinergic receptor agonist carbachol. This AP-induced DSI was mediated by endocannabinoids, as it was prevented by the cannabinoid receptor antagonist AM251 and potentiated by the endocannabinoid transport inhibitor AM404. We also explored the consequences of neocortical DSI on PN excitability by examining the responsiveness of PNs to evoked synaptic stimulation. We found that endocannabinoid-mediated DSI markedly increased PN responsiveness to excitatory synaptic inputs and promoted AP discharge with a time course that paralleled DSI expression. Taken together, our data suggest a role for endocannabinoids in regulating the output of cortical PNs.
Calcium and endocannabinoids in the modulation of inhibitory synaptic transmission
Cell Calcium, 2005
Synapses in the central nervous system can be highly plastic devices, being able to modify their efficacy in relaying information in response to several factors. Calcium ions are often fundamental in triggering synaptic plasticity. Here, we will shortly review the effects induced by postsynaptic increases of calcium concentration at GABAergic and glycinergic synapses. Both postsynaptic and presynaptic mechanisms mediating changes in synaptic strength will be examined. Particular attention will be devoted to phenomena of retrograde signaling and, specifically, to the recently discovered role, played by the endocannabinoid system in retrograde synaptic modulation. (M.A. Diana), pbreges@inmed.univ-mrs.fr (P. Bregestovski). 1 Tel.: 33 1 42 86 38 33.
Differential alteration of hippocampal excitatory synaptic transmission by cannabinoid ligands
Journal of Neuroscience Research, 2009
Cannabinoid compounds affect synaptic activity and plasticity in numerous brain areas by activating CB1 receptors (CB1). In hippocampus, varying results have been obtained on the extent and site of cannabinoid actions on excitatory transmission, ranging from no effect to complete obliteration of synaptic responses. Here we used the rat hippocampal slice preparation to study and compare the effect of various synthetic and endogenous CB1 ligands on excitatory synaptic transmission. The full CB1 agonist WIN55212-2 (WIN2) greatly decreased excitatory synaptic transmission by 62%. The effect of WIN-2 was concentration dependent (EC50 of 200 nM) and completely prevented by CB1 antagonists. The nondegradable partial CB1 agonist R1-methanandamide (mAEA) decreased transmission by 25% and the endocannabinoids 2-arachidonylglycerol (2-AG) and anandamide (AEA) had no significant effect. The action of AEA was improved by inhibiting its degradation but not its transport. The effect of 2-AG was enhanced upon inhibition of COX-2 but remained unchanged with blockade of monoacylglycerol lipase (MAGL). The observed effects were prevented by CB1 antagonists regardless of the ligand used, and paired-pulse paradigms pointed to presynaptic mechanisms of cannabinoid action. Our results show that cannabinoid effects on neuronal activity differ widely according to the CB1 ligand used. We observed large differences between full (synthetic) and partial (endogenous) CB1 agonists in altering synaptic transmission, notably because of the involvement of active degradation mechanisms. V