Endocannabinoids (eCBs) are important retrograde signaling molecules that regulate synaptic strength in many brain areas. They are released by postsynaptic cells and activate presynaptic G protein-coupled type- 1 cannabinoid receptors (CBIRs). CB1R signaling can induce both short-term and long-term depression (STD and LTD). CBIRs are the primary target of psychoactive constituents found in marijuana and have also been implicated in brain reward mechanisms. Previous studies have elucidated two cellular mechanisms that control eCB release: elevation of postsynaptic calcium and activation of postsynaptic phospholipase C-beta (PLCP). We will investigate how calcium and PLC(3 interact to control the activity dependence of eCB signaling at synapses onto cerebellar stellate cells (SCs) in acute brain slices. Interactions between calcium and PLCP are difficult to study without the ability to simultaneously measure postsynaptic calcium and synaptic strength. We will dissect contributions of postsynaptic calcium and PLCP to eCB signaling using electrophysiology, 2-photon calcium imaging and pharmacology. This will allow us to address two important issues regarding the activity dependence of eCB signaling. First, we will examine conditions that permit physiologically relevant patterns of spiking to evoke eCB signaling that induces STD or LTD. Second we will examine eCB signaling in response to brief, high frequency and prolonged, low frequency patterns of synaptic activation. Here, we will determine the contributions of postsynaptic calcium and PLCP to eCB signaling and assay for STD and LTD. Finally, we will investigate the role of eCB signaling in associating presynaptic and postsynaptic patterns of activity. Results from these studies will provide insight into the learning rules for STD and LTD. Understanding eCB signaling in SCs has specific importance for cerebellar function and also general importance for eCB signaling elsewhere in the brain. The endocannabinoid system is an intensely studied therapeutic target, because it is involved in brain areas that control learning, memory, motor coordination, appetite, cognition, pain and addiction. Recently, the first drug targeting brain cannabinoid receptors was introduced as an anti-obesity and smoking cessation treatment. Thus, understanding mechanisms that underlie the richness of endocannabinoid signaling provides promise for the development of novel drugs and therapies.
| Myoga, Michael H; Regehr, Wade G (2011) Calcium microdomains near R-type calcium channels control the induction of presynaptic long-term potentiation at parallel fiber to purkinje cell synapses. J Neurosci 31:5235-43 |
| Myoga, Michael H; Beierlein, Michael; Regehr, Wade G (2009) Somatic spikes regulate dendritic signaling in small neurons in the absence of backpropagating action potentials. J Neurosci 29:7803-14 |
