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

Abstract

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...

Cholinergic and endocannabinoid neuromodulatory effects overlap on neurons of the pedunculopontine nucleus of mice

“…Activation of muscarinic receptors can stimulate endocannabinoid synthesis, as it was shown on cerebellar Purkinje-cells [19] and in the hippocampus [9]. If this is the 13 case in the PPN, activation of M1 receptor increase endocannabinoid synthesis on neurons possessing it, and, in turn, this endocannabinoid acts on astrocytes [11].…”

Acetylcholine, GABA and neuronal networks: A working hypothesis for compensations in the dystrophic brain

“…It was suggested that mAChRs activation selectively targets presynaptic and postsynaptic LTP mechanisms and, though not directly, LTD penetrance could be enhanced indirectly by the prevention of coincident potentiation. Thus, cholinergic signaling in the cerebellum suppresses presynaptic LTP to prevent an upregulation of transmitter release that opposes the reduction of postsynaptic responsiveness (Rinaldo and Hansel, 2013).…”

Muscarinic M1 receptor modulation of synaptic plasticity in nucleus accumbens of wild-type and fragile X mice

“…Both mGluR5 and M 1 mAChR are Gq-coupled receptors, that engage similar downstream plasticity mechanisms 52 . M 1 mAChR regulate inhibitory and excitatory synapses via 2-AG and CB1R [53][54][55][56][57] . Thus, the current data add to the growing list of central synapses where 2-AG is the principal mediator of eCB mediated GPCR synaptic plasticity.…”