Endocannabinoids Control the Induction of Cerebellar LTD

Abstract

The long-term depression (LTD) of parallel fiber (PF) synapses onto Purkinje cells plays a central role in motor learning. Endocannabinoid release and LTD induction both depend upon activation of the metabotropic glutamate receptor mGluR1, require postsynaptic calcium increases, are synapse specific, and have a similar dependence on the associative activation of PF and climbing fiber synapses. These similarities suggest that endocannabinoid release could account for many features of cerebellar LTD. Here we show that LTD induction is blocked by a cannabinoid receptor (CB1R) antagonist, by inhibiting the synthesis of the endocannabinoid 2-arachidonyl glycerol (2-AG), and is absent in mice lacking the CB1R. Although CB1Rs are prominently expressed presynaptically at PF synapses, LTD is expressed postsynaptically. In contrast, a previously described transient form of inhibition mediated by endocannabinoids is expressed presynaptically. This indicates that Purkinje cells release 2-AG that activates CB1Rs to both transiently inhibit release and induce a postsynaptic form of LTD.

Presynaptically expressed long-term depression at cerebellar parallel fiber synapses

“…1). Safo and Regehr [36] reported that the effects of WIN55212-2 on PF to PN synaptic transmission was fully reversible upon application of AM251, while we found that AM251 (at a concentration effective to block the effect of WIN55212-2) did not reverse the WIN55212-2-induced depression of PF calcium transients. The reason for this discrepancy is unclear.…”

“…It has been reported that production of endocannabinoids in PNs is required for cerebellar PF-PN postsynaptic LTD [36]. We examined whether CB1 receptors are involved in preLTD.…”

“…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]. Their inference that endocannabinoids only affected postsynaptic PF-PN LTD was based on the assumption that there is only a postsynaptic form of LTD at this synapse and indirect evidence derived from the lack of change in PPR.…”

Cannabis Use Disrupts Eyeblink Conditioning: Evidence for Cannabinoid Modulation of Cerebellar-Dependent Learning

“…Indeed, it has recently been shown that concurrent parallel fiber/climbing fiber activation of Purkinje cells (which is analogous to convergent CS-US input) leads to short-term depression of the parallel fiber synapse, an effect which is mediated by endocannabinoids (Brenowitz and Regehr, 2005). Such an effect may be crucial for the induction of longer-lasting synaptic plasticity, such as endocannabinoid-mediated long-term depression (LTD; Safo and Regehr, 2005), which itself may represent the neural substrate of EBC (Thompson and Kim, 1996).…”

Central cannabinoid receptors modulate acquisition of eyeblink conditioning

“…CB1Rs are located on the glutamatergic terminals of parallel fibers and the GABAergic terminals of stellate cells and basket cells, and thereby modulate inhibitory and excitatory synaptic transmission to Purkinje cells (Iversen 2003). Activation of CB1Rs is necessary for Purkinje cell LTD (Safo and Regehr 2005). Moreover, Purkinje cell LTD is dependent on release of the endocannabinoid 2-arachidonyl glycerol (2-AG) from Purkinje cells (Safo and Regehr 2005), which results in decreased glutamate release from parallel fibers (Kreitzer and Regehr 2001a,b).…”