Recent studies demonstrate that endocannabinoids act as retrograde messengers, inhibiting synaptic transmission in several brain regions including the cerebellum. In cerebellar Purkinje cells, elevation of postsynaptic calcium evokes release of endocannabinoids which diffuse to presynaptic targets, activating G-protein linked cannabinoid receptors, and suppressing synaptic transmission for tens of seconds. Recent work highlights the widespread importance of endocannabinoid signaling, yet several fundamental issues remain unanswered. We will investigate basic aspects of endocannabinoid signaling, using whole cell recording and calcium imaging techniques in the cerebellar slice preparation. The proposed experiments will (a) investigate mechanisms of endocannabinoid release from Purkinje cell dendrites, (b) characterize physiological and stimulus conditions under which release occurs, and (c) determine the physiological role of retrograde inhibition. These studies will clarify the function of endogenous cannabinoid signaling in the cerebellum and will contribute to therapeutic approaches to neurological disorders that involve disruptions of the cannabinoid system, including Huntington's and Parkinson's disease.
| Brenowitz, Stephan D; Best, Aaron R; Regehr, Wade G (2006) Sustained elevation of dendritic calcium evokes widespread endocannabinoid release and suppression of synapses onto cerebellar Purkinje cells. J Neurosci 26:6841-50 |
| Brenowitz, Stephan D; Regehr, Wade G (2005) Associative short-term synaptic plasticity mediated by endocannabinoids. Neuron 45:419-31 |
