Distributed dopaminergic signaling in the basal ganglia and its relationship to motor disability in Parkinson's disease

Abstract

The degeneration of mesencephalic dopaminergic neurons that innervate the basal ganglia is responsible for the cardinal motor symptoms of Parkinson's disease (PD). It has been thought that loss of dopaminergic signaling in one basal ganglia region - the striatum - was solely responsible for the network pathophysiology causing PD motor symptoms. While our understanding of dopamine (DA)'s role in modulating striatal circuitry has deepened in recent years, it also has become clear that it acts in other regions of the basal ganglia to influence movement. Underscoring this point, examination of a new progressive mouse model of PD shows that striatal dopamine DA depletion alone is not sufficient to induce parkinsonism and that restoration of extra-striatal DA signaling attenuates parkinsonian motor deficits once they appear. This review summarizes recent advances in the effort to understand basal ganglia circuitry, its modulation by DA, and how its dysfunction drives PD motor symptoms.

Figure 1.

The complex basal ganglia circuitry revealed by recent anatomical and functional studies. It should be noted that the SNc dopaminergic neurons innervate both the striatum and extrastriatal nuclei. In each target region, dopamine exerts presynaptic and postsynaptic modulations depending on the type of dopamine receptors expressed. It should also be noted that the direct and indirect pathways do not act in isolation nor are strictly opposing. Abbreviations: ACh, acetylcholine; Ark, arkypallidal neurons; ChI, cholinergic interneurons; DA, dopamine; d/iSPNs, direct/indirect pathway spiny projection neurons; GABA, γ-aminobutyric acid; GI, GABAergic interneurons; glut, glutamate; GPe/i, globus pallidus externa/interna; Pro, prototypic neurons; SNc/r, substantia nigra pars compacta/reticulata; STN, subthalamic nucleus.

Figure 2.

Differential modulation of corticostriatal, thalamostriatal, dopaminergic and cholinergic terminals by DA, ACh and GABA. Note that DA axons and ChIs reciprocally modulate each other. The presence of GABA_B receptors on corticostriatal terminals is well documented. However, its distribution on PT versus IT terminals is unclear. Abbreviations: A2aR, adenosine receptor 2a; AC5, adenylyl cyclase 5; AMPAR, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; BDNF, brain-derived neurotrophic factor; Cav1.3, voltage-gated calcium channel 1.3; CB1R, cannabinoid receptor type 1; CL, central lateral thalamus; D1R, dopamine D1 receptor; D2R, dopamine D2 receptor; eCb, endocannabinoid; GABABR, GABA_B receptor; IT, intratelencephalic neuron; M1R, muscarinic ACh receptor 1; M2/4R, muscarinic ACh receptor 2 or 4; mGluR5, metabotropic glutamate receptor 5; nAChR, nicotinic ACh receptor; NMDAR, N-methyl-D-aspartate receptor; PFN, thalamic parafascicular nucleus; PKA, protein kinase A; PLD, phospholipase D; PT, pyramidal tract neuron; TrkBR, tropomyosin-related kinase B receptor.