Calcium-Dependent Synaptic Plasticity in the Cerebellum

Endocannabinoids (eCBs) are important retrograde messengers that are released from postsynaptic cells in a calcium-dependent manner and activate Gi/o-coupled CB1 cannabinoid receptors (CB1Rs) on presynaptic terminals. CB1Rs suppress neurotransmitter release to regulate synaptic strength throughout the brain on short and long timescales. In the present studies we investigate two important questions regarding eCB signaling in the cerebellum. First, we examine the manner in which spiking activity promotes eCB release in stellate cells (SCs), which are small GABAergic interneurons in the cerebellar cortex. We find that although SCs do not express dendritic voltage-gated sodium channels, action potentials effectively spread into their dendrites and promote calcium influx because they are sufficiently compact. Spiking-evoked dendritic calcium elevations are sufficient to evoke the release of eCBs that transiently suppress their parallel fiber (PF) excitatory synaptic inputs. Moreover, spiking-evoked eCB release interacts with synaptic stimulation to promote associative short-term depression. These findings have specific importance for mechanisms of eCB release during physiologically-relevant patterns of spiking activity as well as general importance for dendritic calcium signaling in small neurons. Next, we investigate the mechanism by which eCBs can control a presynaptic form of long-term potentiation (LTP) at PF to Purkinje cell (PC) synapses (PF-LTP). PF-LTP is mediated by elevations of presynaptic cAMP levels produced by calcium-dependent isoforms of adenylyl cyclase (AC1/8). Retrograde eCB signaling through CB1Rs can inhibit PF-LTP by suppressing AC1/8 activity. We tested the possibility that a reduction in presynaptic calcium influx is sufficient to explain CB1R-dependent inhibition of PF-LTP. We find that PF-LTP is highly sensitive to presynaptic calcium influx. Moreover, R-type calcium channels, but not N-type or P/Q-type calcium channels are important for PF-LTP. Finally, regulation of global calcium signaling within PF terminals is insufficient to explain the calcium dependence of PF-LTP, which suggests a functional colocalization between R-type calcium channels and AC1/8. These findings have specific importance for calcium microdomains near R-type calcium channels and general importance for cAMP-dependent plasticity throughout the brain. Together our studies provide insight into physiological conditions that promote eCB release and functional consequences of retrograde signaling in the brain.