Climbing Fiber-Evoked Endocannabinoid Signaling Heterosynaptically Suppresses Presynaptic Cerebellar Long-Term Potentiation

Beugen, Boeke J. van; Nagaraja, Raghavendra Y.; Hansel, Christian

doi:10.1523/jneurosci.0805-06.2006

Cited by 55 publications

(51 citation statements)

References 35 publications

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“…Our results indicate that mAChR activation has a suppressive effect on LTP induction at PF-Purkinje cell synapses. The blockade of presynaptic LTP via retrograde cannabinoid signaling and CB1R activation is reminiscent of our previous description of a cannabinoid-mediated suppression of LTP resulting from application of the PF-LTP induction protocol (8-Hz, 15-s PF tetanization) combined with CF stimulation at 1-4 Hz (28). Because more prolonged pairing of PF and CF activity can lead to PF-LTD (39), the putative cellular correlate of cerebellar learning (40,41; but see ref.…”

Section: Cholinergic Signaling Modulates Synaptic Plasticity In the Cmentioning

confidence: 67%

“…Because more prolonged pairing of PF and CF activity can lead to PF-LTD (39), the putative cellular correlate of cerebellar learning (40,41; but see ref. 42), and because cannabinoids are required for this process (43), it was hypothesized that the role of cannabinoid signaling in LTD induction is to prevent a simultaneous potentiation of transmitter release from diluting the consequences of postsynaptic depression (28). It is possible that in the vestibulocerebellum muscarinic input functions in a similar capacity as that of the CF; that is, it is delivered in a context-dependent fashion and decreases the likelihood of induction for different forms of LTP, potentially enhancing the overall penetrance of LTD. Our data show that the LTD mechanism itself is not affected by mAChR activation, which had seemed possible considering that mAChRs share downstream effectors with mGluR1 (PLC/DAG signaling cascade) in a signaling pathway that is essential for cerebellar LTD (44,45).…”

Section: Cholinergic Signaling Modulates Synaptic Plasticity In the Cmentioning

confidence: 99%

“…Cannabinoids are released from the postsynaptic cells and bind to cannabinoid 1 receptors (CB1Rs) on presynaptic terminals, where they diminish neurotransmitter release probability through a G i/o -coupled pathway (25). In addition to transiently reducing synaptic strength (26,27), cannabinoid release has been shown to inhibit a presynaptic form of long-term potentiation (LTP) at PF-Purkinje cell synapses (PF-LTP) by suppressing the activation of adenylyl cyclase (28). Here we demonstrate that cholinergic signaling and the activation of mAChRs on Purkinje cells blocks the induction of presynaptic PF-LTP.…”

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confidence: 99%

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Muscarinic acetylcholine receptor activation blocks long-term potentiation at cerebellar parallel fiber–Purkinje cell synapses via cannabinoid signaling

Rinaldo

Hansel

2013

Proc. Natl. Acad. Sci. U.S.A.

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Muscarinic acetylcholine receptors (mAChRs) are known to modulate synaptic plasticity in various brain areas. A signaling pathway triggered by mAChR activation is the production and release of endocannabinoids that bind to type 1 cannabinoid receptors (CB1R) located on synaptic terminals. Using whole-cell patch-clamp recordings from rat cerebellar slices, we have demonstrated that the muscarinic agonist oxotremorine-m (oxo-m) blocks the induction of presynaptic long-term potentiation (LTP) at parallel fiber (PF)-Purkinje cell synapses in a CB1R-dependent manner. Under control conditions, LTP was induced by delivering 120 PF stimuli at 8 Hz. In contrast, no LTP was observed when oxo-m was present during tetanization. PF-LTP was restored when the CB1R antagonist N-1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-1-piperidinyl-1H-pyrazole-3-carboxamide (AM251) was coapplied with oxo-m. Furthermore, the suppressive effect of oxo-m on PF-LTP was abrogated by the GDP analog GDP-β-S (applied intracellularly), the phospholipase C inhibitor U-73122, and the diacylglycerol lipase inhibitor tetrahydrolipstatin (THL), suggesting that cannabinoid synthesis results from the activation of G q -coupled mAChRs present on Purkinje cells. The oxo-m-mediated suppression of LTP was also prevented in the presence of the M3 receptor antagonist DAU 5884, and was absent in M1/M3 receptor double-KO mice, identifying M3 receptors as primary oxo-m targets. Our findings allow for the possibility that cholinergic signaling in the cerebellum-which may result from long-term depression (LTD)-related disinhibition of cholinergic neurons in the vestibular nuclei-suppresses presynaptic LTP to prevent an up-regulation of transmitter release that opposes the reduction of postsynaptic responsiveness. This modulatory capacity of mAChR signaling could promote the functional penetrance of LTD.vestibulocerebellum | learning | retrograde signaling L ong-lasting changes in synaptic efficacy at parallel fiber (PF)-Purkinje cell synapses are widely considered to be a requisite for cerebellar motor learning (1-3). Neuromodulators that can shift the induction probabilities for various types of plasticity at this synapse may thus fine-tune the conditions under which motor learning can occur. One neuromodulator that may function in this role is acetylcholine, which has been shown to affect synaptic plasticity in the hippocampus, visual cortex, and dorsal cochlear nucleus (DCN; a cerebellum-like structure) through the activation of muscarinic acetylcholine receptors (mAChRs) (4-8). There are five known isoforms of mAChRs (designated M1-5), each of which exhibits a heterogeneous distribution pattern across different brain areas (9-11). All five isoforms are expressed in the cerebellar cortex (12) and are found predominantly in lobules IX and X (13), which form the bulk of the vestibulocerebellum. Cholinergic cerebellar afferents to this area are believed to originate from the vestibular nuclei of the brainstem (14, 15), and within these lobules the action of ace...

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Section: Cholinergic Signaling Modulates Synaptic Plasticity In the Cmentioning

confidence: 67%

Section: Cholinergic Signaling Modulates Synaptic Plasticity In the Cmentioning

confidence: 99%

mentioning

confidence: 99%

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Muscarinic acetylcholine receptor activation blocks long-term potentiation at cerebellar parallel fiber–Purkinje cell synapses via cannabinoid signaling

Rinaldo

Hansel

2013

Proc. Natl. Acad. Sci. U.S.A.

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“…In contrast to the form of LTD described in this study, these CB1 The role of endocannabinoids in PF long-term plasticity had been less clear. It has been shown that climbing fiberevoked endocannabinoid signaling can suppress PF presynaptic LTP [43]. Regehr and coworkers found that CB1 receptor activation did not cause persistent modification of presynaptic PF mechanisms but proposed that CB1 receptors control the expression of postsynaptic PF-PN LTD [6,36].…”

Section: Demonstration Of Preltdmentioning

confidence: 99%

Presynaptically expressed long-term depression at cerebellar parallel fiber synapses

Qiu

Knöpfel

2008

Pflugers Arch - Eur J Physiol

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Plasticity at synapses between parallel fiber (PF) and Purkinje neurons (PN) is widely accepted as a cellular model for certain forms of cerebellar learning. Although PF-PN synapses are known to express bidirectional longterm plasticity at the postsynaptic site, long-term plasticity at the presynaptic site is currently limited to potentiation of the synapses. In this paper, we report on presynaptically expressed PF long-term depression (preLTD) that is observed when presynaptically expressed PF long-term potentiation (preLTP) is pharmacologically prevented. PF preLTD is most efficiently induced by 4 Hz PF stimulation and requires activation of cannabinoid CB1 receptors. Our results indicate that, during preLTD induction, endocannabinoids are released in an NMDA receptor-dependent, but not mGlu1 receptor-dependent, fashion. We conclude that bidirectional plasticity mechanisms exist for both presynaptic and postsynaptic components of cerebellar learning.

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“…However, there is one report that suggested that an NMDA/NO cascade is involved in presynaptically expressed PF-PN LTP (Jacoby et al, 2001). Any stringent evaluation of presynaptic PF-PN LTP has been hindered by the fact that the locus of presynaptic expression could only be indirectly inferred from changes in paired-pulse facilitation (Salin et al, 1996;Storm et al, 1998;Lonart et al, 2003;van Beugen et al, 2006) and an increase in the frequency of miniature EPSCs after forskolin application (Chen and Regehr, 1997;Jacoby et al, 2001). …”

Section: Introductionmentioning

confidence: 99%

An NMDA Receptor/Nitric Oxide Cascade in Presynaptic Parallel Fiber–Purkinje Neuron Long-Term Potentiation

Qiu¹,

Knöpfel²

2007

J. Neurosci.

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Climbing Fiber-Evoked Endocannabinoid Signaling Heterosynaptically Suppresses Presynaptic Cerebellar Long-Term Potentiation

Cited by 55 publications

References 35 publications

Muscarinic acetylcholine receptor activation blocks long-term potentiation at cerebellar parallel fiber–Purkinje cell synapses via cannabinoid signaling

Muscarinic acetylcholine receptor activation blocks long-term potentiation at cerebellar parallel fiber–Purkinje cell synapses via cannabinoid signaling

Presynaptically expressed long-term depression at cerebellar parallel fiber synapses

An NMDA Receptor/Nitric Oxide Cascade in Presynaptic Parallel Fiber–Purkinje Neuron Long-Term Potentiation

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