Dopamine Signaling in Substantia Nigra and Its Impact on Locomotor Function-Not a New Concept, but Neglected Reality

Abstract

The mechanistic influences of dopamine (DA) signaling and impact on motor function are nearly always interpreted from changes in nigrostriatal neuron terminals in striatum. This is a standard practice in studies of human Parkinson's disease (PD) and aging and related animal models of PD and aging-related parkinsonism. However, despite dozens of studies indicating an ambiguous relationship between changes in striatal DA signaling and motor phenotype, this perseverating focus on striatum continues. Although DA release in substantia nigra (SN) was first reported almost 50 years ago, assessment of nigral DA signaling changes in relation to motor function is rarely considered. Whereas DA signaling has been well-characterized in striatum at all five steps of neurotransmission (biosynthesis and turnover, storage, release, reuptake, and post-synaptic binding) in the nigrostriatal pathway, the depth of such interrogations in the SN, outside of cell counts, is sparse. However, there is sufficient evidence that these steps in DA neurotransmission in the SN are operational and regulated autonomously from striatum and are present in human PD and aging and related animal models. To complete our understanding of how nigrostriatal DA signaling affects motor function, it is past time to include interrogation of nigral DA signaling. This brief review highlights evidence that changes in nigral DA signaling at each step in DA neurotransmission are autonomous from those in striatum and changes in the SN alone can influence locomotor function. Accordingly, for full characterization of how nigrostriatal DA signaling affects locomotor activity, interrogation of DA signaling in SN is essential.

Keywords: Parkinson’s disease; aging; dopamine; dopamine receptor; nigrostriatal; phosphorylation; reuptake; striatum; substantia nigra; tyrosine hydroxylase.

Figure 1

Molecular changes in components of dopamine (DA) signaling in substantia nigra (SN) are autonomous from those in striatum during aging and coincide with decreasing locomotor function. Unlike PD, loss of tyrosine hydroxylase (TH) protein and tissue DA in striatum is substantially less and more highly variable (-) in aging, with maximum loss of ~50% being the most ever reported [164,165,166,167,168,169]. Conversely, in the SN, there are several aging-related changes occurring at the biosynthesis and receptor levels. Loss of the DA D₁ receptor (D₁) occurs in the middle to late-middle stages of the lifespan and temporally coincides with the onset of locomotor decline [149]. Loss of TH protein progresses (→) in the SN toward the latter (aged) part of the lifespan, with steadily decreasing DA tissue content [84,148,151,159,160,161,162,163,164,165,166]. Notably, there is also a decrease in site-specific TH phosphorylation at ser31 (ser31 pTH), but not at ser40 (ser40 pTH), that occurs only in the SN [151]. Aging-related loss of nigral TH protein and tissue DA is comparable to loss at the onset of locomotor impairment in PD [19], suggesting that DA tissue losses from decreased ser31 TH phosphorylation and TH protein are mechanisms of hypokinesia seen in aging.

Figure 2

Disparate molecular changes in dopamine (DA) signaling components in substantia nigra (SN) and striatum in response to neuronal loss and relation to decreased locomotor function. Induction of nigrostriatal neuron loss by 6-OHDA produces a progressive loss of neurons over 4 weeks. Loss of tyrosine hydroxylase (TH) protein in SN is less than the magnitude of loss in the striatum at the earlier time points post-lesion, and tissue DA loss is substantially and consistently less in the SN than in striatum. In response to TH loss, there is a site-specific increase in TH phosphorylation at ser31 (ser31 pTH), not ser40 (ser40 pTH), restricted to the SN; whereas in striatum, there is a progressive decrease in ser31 pTH. This increase in ser31 pTH in the SN offsets the progressive loss of TH therein to keep DA loss at a lower level than TH. As DA tissue loss increases in the SN, the DA D₁ receptor (D1) increases expression at the latter stages of neuron loss. The increases in both ser31 TH phosphorylation and D1 in the SN are compensatory mechanisms to delay the onset of locomotor impairment and alleviate its severity.

Figure 3

Compensatory response in substantia nigra (SN) to maintain dopamine (DA) signaling. (A) Early stage of nigrostriatal neuron loss. During nigrostriatal neuron loss, tyrosine hydroxylase (TH) protein loss (downward arrow) in SN precedes neuron loss. To maintain DA tissue levels, TH phosphorylation at ser31 (Ser31P) increases (beige upward arrow), offsetting DA loss that would otherwise occur (as seen in striatum) [22]. Adequate tissue DA levels maintain sufficient DA release in SN pars compacta (SNc) to activate post-synaptic DA D₁ receptors (D₁), thus enabling GABA release (red arrows) from striatonigral terminals. This release from striatonigral neurons in SN pars reticulata (SNr) mitigates tonic GABA release from the SNr efferent on the thalamocortical neurons (TCN) to promote locomotor activity via glutamate release (green arrows). (B) Late stage of nigrostriatal neuron loss. Although ser31P is still increased, TH protein progresses further and is sufficient to diminish DA tissue levels, although DA loss is still less than TH protein loss [22]. The decrease in DA tissue content diminishes release capacity. In response, the D1 is upregulated (beige upward arrow) on post-synaptic striatonigral terminals to compensate for decreased synaptic DA levels. The overall plasticity of increased DA biosynthesis and D₁ expression in the SN is hypothesized to mitigate the severity of bradykinesia/hypokinesia that would be expected from severe TH protein and nigrostriatal neuron loss.