Endocannabinoids Inhibit Transmission at Granule Cell to Purkinje Cell Synapses by Modulating Three Types of Presynaptic Calcium Channels

Brown, Solange P.; Safo, Patrick; Regehr, Wade G.

doi:10.1523/jneurosci.0918-04.2004

Cited by 141 publications

(136 citation statements)

References 49 publications

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“…In this case, however, the cannabimimetic agonists act directly on the Ca v 3 channel isoforms and independently of CB1R activation. Also the lack of effects on R-type channels is in agreement with previous works reporting no action on somatic R-type channels in central neurons [22,38] but it is at variance with the observation that presynaptic R-type channels are effectively inhibited by cannabimimetic agonists at the granule cell-Purkinje neuron synapses [39]. These contrasting results reflect most likely the heterogeneous nature of neuronal R-type channels [40].…”

Section: L-type Versus Non-l-type Channel Modulation By Cannabinoidssupporting

confidence: 89%

L-type channel inhibition by CB1 cannabinoid receptors is mediated by PTX-sensitive G proteins and cAMP/PKA in GT1-7 hypothalamic neurons

et al. 2009

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a b s t r a c tUsing immortalized hypothalamic GT1-7 neurons, which express the CB1 cannabinoid receptor (CB1R) and three Ca 2+ channel types (T, R and L), we found that the CB1R agonist WIN 55,212-2 inhibited the voltage-gated Ca 2+ currents by about 35%. The inhibition by WIN 55,212-2 (10 M) was reversible and prevented by nifedipine (3 M), suggesting a selective action on L-type Ca 2+ channels (LTCCs). WIN 55,212-2 action exhibited all the features of voltage-independent Ca 2+ channel modulation: (1) no changes of the activation kinetics, (2) equal depressive action at all potentials and (3) no facilitation following strong prepulses. At variance with WIN 55,212-2, the CB1R inverse agonist AM-251 (10 M) caused 20% increase of Ca 2+ currents. The inhibition of LTCCs by WIN 55,212-2 was prevented by overnight PTX-incubation and by intracellular perfusion with GDP-␤-S. The latter caused also a 20% Ca 2+ current up-regulation. WIN 55,212-2 action was also prevented by application of the PKA-blocker H89 or by loading the neurons with 8-CPT-cAMP. Our results suggest that LTCCs in GT1-7 neurons are partially inhibited at rest due to a constitutive CB1R activity removed by AM-251 and GDP-␤-S. Activation of CB1R via PTX-sensitive G proteins and cAMP/PKA pathway selectively depresses LTCCs that critically control the synchronized spontaneous firing and pulsatile release of gonadotropin-releasing hormone in GT1-7 neurons.

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Section: L-type Versus Non-l-type Channel Modulation By Cannabinoidssupporting

confidence: 89%

L-type channel inhibition by CB1 cannabinoid receptors is mediated by PTX-sensitive G proteins and cAMP/PKA in GT1-7 hypothalamic neurons

et al. 2009

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“…Because acute activation of CB1R located presynaptically on PFs modulates granule cell synaptic release (Takahashi and Linden, 2000;Brown et al, 2004;Daniel et al, 2004), we investigated whether chronic cannabinoid treatment would alter PF-PC synaptic properties. The relationship between excitatory postsynaptic current (EPSCs) amplitudes (output) as a function of PF stimulus intensity (input) for each neuron was compared in cerebellar slices prepared from mice chronically exposed to THC (10 mg/kg) or to its vehicle ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Accumulation of glutamate is required for the activation of mGluR1-mediated EPSCs in PCs (Batchelor and Garthwaite, 1993;Tempia et al, 1998;Brown et al, 2004). We evaluated whether the induction of slow mGluR1-mediated EPSCs was facilitated in tolerant mice by delivering a highfrequency train of stimuli to PFs (e.g., 1-10 stimuli at 100 Hz) in the presence of ionotropic GABA and glutamate antagonists (100 M picrotoxin, 40 M DL-APV, 20 M DNQX).…”

Section: Facilitated Induction Of Slow Metabotropic Glutamate Receptomentioning

confidence: 99%

ERK-Dependent Modulation of Cerebellar Synaptic Plasticity after Chronic Δ9-Tetrahydrocannabinol Exposure

Tonini¹,

Ciardo²,

Cerovic³

et al. 2006

J. Neurosci.

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Chronic exposure to ⌬9-tetrahydrocannabinol (THC) induces tolerance to cannabinoid-induced locomotor effects, which are mediated by cannabinoid receptors (CB1Rs) located in motor control regions, including the cerebellum. There is substantial evidence of cerebellar CB1R molecular adaptation and modifications in receptor signaling after prolonged cannabinoid exposure. However, very little is known about the effects of chronic cannabinoid administration on cerebellar synaptic plasticity, which may contribute to the development of cannabinoid behavioral tolerance.In the cerebellar cortex, activation of CB1R inhibits excitatory synaptic transmission at parallel fiber ( In summary, we provide evidence for ERK-dependent modulatory mechanisms at PF-PC synapses after chronic THC administration. This contributes to generation of forms of pathological synaptic plasticity that might play a role in cannabinoid dependence.

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“…Maximal inhibition was reached after B20 min. It has been repeatedly observed in the past that the effects of cannabinoids develop slowly in brain slices, probably due to the high lipophilicity of cannabinoids (Szabo et al, 1998;Brown et al, 2004).…”

Section: Effect Of the Exogenous Cannabinoid Agonist Win55212-2 On Gamentioning

confidence: 99%

Exogenous and Endogenous Cannabinoids Suppress Inhibitory Neurotransmission in the Human Neocortex

Kovacs

Knop

Urbanski

et al. 2011

Neuropsychopharmacol

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Activation of CB 1 receptors on axon terminals by exogenous cannabinoids (eg, D 9 -tetrahydrocannabinol) and by endogenous cannabinoids (endocannabinoids) released by postsynaptic neurons leads to presynaptic inhibition of neurotransmission. The aim of this study was to characterize the effect of cannabinoids on GABAergic synaptic transmission in the human neocortex. Brain slices were prepared from neocortical tissues surgically removed to eliminate epileptogenic foci. Spontaneous GABAergic inhibitory postsynaptic currents (sIPSCs) were recorded in putative pyramidal neurons using patch-clamp techniques. To enhance the activity of cannabinoidsensitive presynaptic axons, muscarinic receptors were continuously stimulated by carbachol. The synthetic cannabinoid receptor agonist WIN55212-2 decreased the cumulative amplitude of sIPSCs. The CB 1 antagonist rimonabant prevented this effect, verifying the involvement of CB 1 receptors. WIN55212-2 decreased the frequency of miniature IPSCs (mIPSCs) recorded in the presence of tetrodotoxin, but did not change their amplitude, indicating that the neurotransmission was inhibited presynaptically. Depolarization of postsynaptic pyramidal neurons induced a suppression of sIPSCs. As rimonabant prevented this suppression, it is very likely that it was due to endocannabinods acting on CB 1 receptors. This is the first demonstration that an exogenous cannabinoid inhibits synaptic transmission in the human neocortex and that endocannabinoids released by postsynaptic neurons suppress synaptic transmission in the human brain. Interferences of cannabinoid agonists and antagonists with synaptic transmission in the cortex may explain the cognitive and memory deficits elicited by these drugs.

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Endocannabinoids Inhibit Transmission at Granule Cell to Purkinje Cell Synapses by Modulating Three Types of Presynaptic Calcium Channels

Cited by 141 publications

References 49 publications

L-type channel inhibition by CB1 cannabinoid receptors is mediated by PTX-sensitive G proteins and cAMP/PKA in GT1-7 hypothalamic neurons

L-type channel inhibition by CB1 cannabinoid receptors is mediated by PTX-sensitive G proteins and cAMP/PKA in GT1-7 hypothalamic neurons

ERK-Dependent Modulation of Cerebellar Synaptic Plasticity after Chronic Δ9-Tetrahydrocannabinol Exposure

Exogenous and Endogenous Cannabinoids Suppress Inhibitory Neurotransmission in the Human Neocortex

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