UCSF

The basal ganglia are a network of subcortical brain nuclei important for action selection and motor learning. Excitatory synapses onto projection neurons in the striatum, the input nucleus of the basal ganglia, are a major site of long-term synaptic plasticity. This plasticity has the potential to powerfully regulate motor function by setting the gain on the incoming cortical signals that drive basal ganglia circuits. Endocannabinoid-dependent long-term depression (eCB-LTD) is the best characterized form of striatal plasticity, but the mechanisms governing its normal regulation and pathological dysregulation are not well understood. This thesis examines the molecular mechanisms underlying striatal eCB-LTD. It focuses on eCB-LTD at excitatory synapses onto a subset of striatal projection neurons, or medium spiny neurons (MSNs), the "indirect-pathway" MSNs. These MSNs express dopamine D2 and adenosine A2A receptors and project to the external segment of the globus pallidus. In this thesis, I characterize two distinct biochemical signaling pathways mediating eCB production in striatal indirect-pathway MSNs: a PLCβ- and DAG lipase-dependent pathway that is engaged by low-frequency stimulation, and a novel Src- and PLD-dependent pathway that is engaged by high-frequency stimulation. Endocannabinoid production through both signaling pathways is modulated by dopamine D2 and adenosine A2A receptors, acting through cAMP/PKA. I identify Regulator of G-protein Signaling 4 (RGS4) as a key link between D2/A2A signaling and eCB mobilization pathways. Behaviorally, I find that indirect-pathway eCB-LTD likely underlies at least some of the stimulant properties of A2A receptor antagonists and that the loss of indirect-pathway eCB-LTD may mediate the development of parkinsonian motor deficits following dopamine depletion. In experiments using RGS4 knockout mice, which in contrast to wildtype mice exhibit normal eCB-LTD following dopamine depletion, I show that the loss of RGS4 leads to fewer behavioral deficits after dopamine depletion, suggesting that inhibition of RGS4 may be an effective non-dopaminergic strategy for treating Parkinson's disease.