Dopaminergic modulation of striatal function and Parkinson's disease

Abstract

The striatum is richly innervated by mesencephalic dopaminergic neurons that modulate a diverse array of cellular and synaptic functions that control goal-directed actions and habits. The loss of this innervation has long been thought to be the principal cause of the cardinal motor symptoms of Parkinson's disease (PD). Moreover, chronic, pharmacological overstimulation of striatal dopamine (DA) receptors is generally viewed as the trigger for levodopa-induced dyskinesia (LID) in late-stage PD patients. Here, we discuss recent advances in our understanding of the relationship between the striatum and DA, particularly as it relates to PD and LID. First, it has become clear that chronic perturbations of DA levels in PD and LID bring about cell type-specific, homeostatic changes in spiny projection neurons (SPNs) that tend to normalize striatal activity. Second, perturbations in DA signaling also bring about non-homeostatic aberrations in synaptic plasticity that contribute to disease symptoms. Third, it has become evident that striatal interneurons are major determinants of network activity and behavior in PD and LID. Finally, recent work examining the activity of SPNs in freely moving animals has revealed that the pathophysiology induced by altered DA signaling is not limited to imbalance in the average spiking in direct and indirect pathways, but involves more nuanced disruptions of neuronal ensemble activity.

Keywords: Dopamine; Interneurons; Levodopa-induced dyskinesia; Parkinson’s disease; Striatum; Synaptic plasticity.

Figure 1.

Postsynaptic functions of DA signaling in SPNs. Arrowheads indicate positive regulation and black circles indicate negative regulation. In iSPNs, D2R activation suppresses intrinsic excitability by modulating ion channels, reduces moment-to-moment glutamate transmission, and promotes LTD induction; in dSPNs, D1R activation increases intrinsic excitability (partly through inhibiting N- and P- type calcium channels and suppressing small-conductance calcium-activated potassium channels (SK channels)(Surmeier et al. 1995; Vilchis et al. 2000)) , enhances glutamate transmission, and promotes LTP. Presynaptic or indirect, interneuron-mediated functions of DA are not illustrated here.

Figure 2.

Schematic depicting signaling pathways mediating long-term synaptic plasticity in striatal SPNs. Black arrowheads indicate positive regulation and black circles indicate negative regulation. G_i-coupled D2R and M4R promote eCB-mediated presynaptic LTD and suppress postsynaptic LTP in iSPNs and dSPNs, respectively. On the other hand, D1R and A2aR promote LTP and inhibit presynaptic LTD in dSPNs and iSPNs, respectively. NO released by PLTS interneurons induces a cGMP-dependent, postsynaptic form of LTD. Abbreviations: 2-AG, 2-arachidonoylglycerol; A2aR, adenosine receptor 2a; AC5, adenylyl cyclase 5; Akt, Protein Kinase B; CaMKII, Ca²⁺/calmodulin-dependent protein kinase II; cAMP, 3′−5′-cyclic adenosine monophosphate; cGMP, 3′−5′-cyclic guanosine monophosphate; D1R, dopamine D1 receptor; D2R, dopamine D2 receptor; DAG, 1,2-diacylglycerol; DARPP-32, dopamine- and cAMP-regulated phosphoprotein of 32 kDa; DGLα, diacylglycerol lipase α; eCBs, endocannabinoids; ERK, extracellular signal-regulated kinase; M4R, muscarinic receptor 4; MEK, mitogen-activated protein kinase kinase; mGluR5, metabotropic glutamate receptor 5; NMDAR, N-methyl-D-aspartate receptor; NO, nitric oxide; PI3K, phosphatidylinositide 3-kinase; PKA, protein kinase A; PLCβ, phospholipase Cβ; PLD, phospholipase D; PP1, protein phosphatase 1; RGS4, regulator of G-protein signaling 4; Src, Src-family kinases; TrkBR, tropomyosin related kinase B receptor.