title: Climbing fiber-evoked endocannabinoid signaling heterosynaptically suppresses presynaptic cerebellar long-term potentiation.
abstract: Endocannabinoid signaling has been demonstrated to mediate depolarization-induced suppression of excitation at climbing fiber (CF) and parallel fiber (PF) synapses onto cerebellar Purkinje cells. Here, we show that CF-evoked release of cannabinoids (CBs) additionally suppresses a presynaptic form of long-term potentiation (LTP) at PF synapses. PF-LTP can be induced by 8 Hz PF tetanization but is blocked when the PF tetanization is paired with 4 or 1 Hz CF coactivation. CF activity can be substituted for by bath application of the CB receptor agonist WIN55,212-2 [R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl) methanone]. In the presence of the CB1 receptor antagonist AM251 [N-1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-1-piperidinyl-1H-pyrazole-3-carboxamide], CF activity no longer suppresses PF-LTP. Presynaptic potentiation can also be obtained by the adenylyl cyclase activator forskolin. WIN55,212-2 blocked this forskolin-mediated enhancement, showing that CB1 receptor activation interferes with the adenylyl cyclase-protein kinase A cascade, which participates in LTP induction. CF activity has been described to promote the induction of postsynaptic PF-long-term depression (LTD) and to impair postsynaptic PF-LTP. Our observation that CF activity blocks the induction of presynaptic LTP suggests that the CF input controls all forms of presynaptic and postsynaptic PF plasticity and that CF activity provides a "safety lock" to prevent an enhancement of transmitter release while postsynaptic AMPA receptor function is downregulated during LTD.
authors.affiliation: Department of Neuroscience, Erasmus University Medical Center, 3000 DR Rotterdam, The Netherlands.
authors.forename: Boeke J
authors.initials: BJ
authors.lastname: van Beugen
authors.forename: Raghavendra Y
authors.initials: RY
authors.lastname: Nagaraja
authors.forename: Christian
authors.initials: C
authors.lastname: Hansel
mesh_terms: D000200:Action Potentials / Q000502:physiology*; D000818:Animals; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism*; D002478:Cells, Cultured; D002531:Cerebellum / Q000502:physiology; D063388:Endocannabinoids; D005071:Evoked Potentials / Q000502:physiology; D017774:Long-Term Potentiation / Q000502:physiology*; D009415:Nerve Net / Q000502:physiology*; D017729:Presynaptic Terminals / Q000502:physiology*; D011689:Purkinje Cells / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology; D009435:Synaptic Transmission / Q000502:physiology*
chemical_list: D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids