Title: The role of endocannabinoids in synaptic plasticity at the granule cell to purkinje cell synapse
Description: At many central synapses, endocannabinoids are synthesized and released by the postsynaptic cell to retrogradely modulate synaptic strength. In this thesis, I examine the mechanisms of endocannabinoids for short term synaptic plasticity and the role of endocannabinoids in long term plasticity. In chapter 2, I examined how activation of the type I cannabinoid receptor (CB1R) inhibits presynaptic calcium influx. Using fluorescent imaging and electrophysiological approaches, I show that activation of CB1R does not activate potassium channels that can truncate the presynaptic action potential waveform. Rather, we show that CB1R activation inhibits the voltage gated calcium channels present on the presynaptic boutons. In chapter 3, I explore the mechanisms that control the time course of the endocannabinoids. Inhibition of the enzymes that hydrolyze endocannabinoids, fatty acid amide hydrolase and monoglyceride lipase does not alter the time course of DSE. Rather, it is likely that compensatory inactivation pathways can substitute for the activity of the two major hydrolytic enzymes to maintain the time course of DSE. In chapter 4, I examine the role of endocannabinoids during induction of cerebellar long term depression (LTD). I show that activation of CB1R is required during induction of cerebellar LTD.2 arachidonyl glycerol, which is one of the two central endocannabinoids is released during the induction of LTD. In chapter 5, I examine how systematic variation of the timing between the parallel fiber (PF) and the climbing fiber (CF) during induction of long term plasticity can affect the magnitude of LTD. I demonstrate peak LTD is induced when the PF activity precede the climbing fiber stimulus by 80 ms. These studies contribute to our understanding of the role of endocannabinoids during synaptic plasticity.