CB1 receptors mediate metaplasticity in the cerebellar circuit - Project Summary: The long-term goal of this project is to understand how type 1 cannabinoid receptors (CB1 receptors) regulate synaptic plasticity and learning in the cerebellar circuit. Long-term changes in synaptic strength are a primary cellular mechanism by which neuronal circuits learn, adapt, and store information. However, synaptic plasticity itself must be regulated to provide a balance between response acquisition/adaptation and memory storage/circuit stability. We hypothesize that long-term synaptic plasticity in the cerebellar circuit is regulated by activity-dependent changes in CB1 receptor expression. CB1 receptors are highly expressed at presynaptic terminals of many brain circuits involved in learning and motor coordination, including the cerebellum. At parallel fiber synapses, CB1 receptors are required for induction of both long-term potentiation (LTP) and long-term depression (LTD), process that are widely believed to be a cellular correlate of behavioral learning in the cerebellum. Our recent work and preliminary data have shown that CB1 receptors at parallel fiber synapses are down-regulated following physiological patterns of activity, demonstrating that CB1 receptor expression is a plastic property of the synapses. We will show that activity-dependent down-regulation of presynaptic CB1 receptors reduces the magnitude and/or probability of both LTP and LTD at parallel fiber synapses. We propose that down-regulation of CB1 receptors is a critical step in cerebellar learning that reduces future plasticity at modified synapses and allows for fine- tuning or storage of motor responses. This work will lay the groundwork of basic cellular physiology for understanding changes in CB1 receptor expression in physiological and pathophysiological conditions. Furthermore, we will demonstrate that presynaptic CB1 receptors control the gain of synaptic plasticity in the cerebellum. This work will be critical for understanding how synaptic plasticity is regulated in neuronal circuits and potentially dysregulated in conditions that alter the endocannabinoid system, including epilepsy, depression, and spinocerebellar ataxia. Aim 1: Investigate whether CB1 receptor expression determines LTP/LTD amplitude. Hypothesis: The magnitude of long-term plasticity at parallel fiber synapses is directly related to CB1R activity. Aim 2: Determine the effects of cerebellar learning on CB1 receptor expression. Hypothesis: Reduction of CB1R expression at PF synapses during cerebellar learning or synaptic plasticity is necessary for proper memory formation and retention. Aim3: Determine the mechanisms and signaling pathways required for CB1 receptor plasticity. Hypothesis: CB1R activity is reduced by GRK-mediated internalization and increased 2AG metabolism.
