Dopaminergic modulation of striatal networks in health and Parkinson's disease

Abstract

In the last couple of years, there have been significant advances in our understanding of how dopamine modulates striatal circuits underlying goal-directed behaviors and how therapeutic interventions intended to normalize disordered dopaminergic signaling can go awry. This review summarizes some of the advances in this field with a translational focus on Parkinson's disease.

Figure 1

Circuit diagram depicting basal ganglia circuitry and forms of presynaptic LTD and postsynaptic LTP. The blue blowout to the left of the circuit diagram highlights features of D1 receptor expressing dSPNs (top) and D2 receptor expressing iSPNs (bottom) with dSPNs having larger dendritic arbors than iSPNs. Both dSPNs and iSPNs receive glutamatergic input from the cortex and thalamus; cortical innervation is primarily axospinous and thalamic axodendritic as depicted, albeit not exclusively.

Figure 2

Schematic depicting hypothesized pathways mediating synaptic plasticity in striatal SPNs. Signal transduction pathways mediating the effects of activation of G_s-coupled D1R/A2aR, G_i-coupled M4R/D2R, G_q-coupled mGluR5, and tyrosine kinase TrkB receptor. Note that high PKA activity inhibits G_q-coupled mGluR5 signaling via RGS4. This inhibition effectively prevents the mobilization of both 2-AG and AEA [35**]. Activation of CaMKII suppresses striatal DGLα activity [37*]. Elevating cAMP/PKA signaling promotes NMDAR-mediated Ca²⁺ permeability [38*]. Black arrowheads depict positive regulation and black circles depict negative regulation. Abbreviations: 2-AG, 2-Arachidonoylglycerol; A2aR, adenosine receptor 2a; AC5, adenylyl cyclase 5; AEA, anandamide; Akt, Protein Kinase B; CaMKII, Ca²⁺/calmodulin-dependent protein kinase II; cAMP, 3′-5′-cyclic adenosine monophosphate; DAG, 1,2-diacylglycerol; D1R, dopamine D1 receptor; D2R, dopamine D2 receptor; ERK, extracellular signal-regulated kinase; M4R, muscarinic receptor 4; NMDAR, N-methyl-D-aspartate receptor; MEK, mitogen-activated protein kinase kinase; mGluR5, metabotropic glutamate receptor 5; NMDA receptor; PI3K, phosphatidylinositide 3-kinases; PIP₂, Phosphatidylinositol 4,5-bisphosphate; PKA, protein kinase A; PLCβ, phospholipase Cβ; PLD, phospholipase D; RGS4, regulator of G-protein signaling 4; Src, Src-family kinases; TrkBR, tropomyosin related kinase B receptor.