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.

Changes in Striatal Medium Spiny Neuron Morphology Resulting from Dopamine Depletion Are Reversible

“…In previous work by others, notable differences were observed between D1-MSN, D2-MSN, and D1/D2 double positive MSN. In D2-MSN, a reduction in spine density was observed already 2-3 weeks after dopamine depletion whereas in D1-MSN spine density was only reduced with more chronic dopamine depletion [7,14,21,22,31,32].…”

“…Homeostatic plasticity allows neuronal networks to maintain a stable rate of activity when synapses change [5]. This has been studied mainly during development and learning [5,6], but also in the course of neurological and psychiatric diseases [7][8][9][10]. In humans and animal models, chronic dopaminergic depletion and substitution can induce plastic changes that differ from acute effects and that are potentially mediated by homeostatic plasticity mechanisms.…”

Pathway-specific deregulation of striatal excitatory synapses in LRRK2 mutations

“…Similarly, evidence of increased synaptic PKA activities was observed in +/RC and not +/GS striatal synaptic fractions. This increased PKA activity in the RC synapses is expected to positively correlate with elevations in dSPNs signaling 38 . Specifically, phosphorylation of GluA1 at Ser 845 by PKA facilitates the targeting of the receptors to extrasynaptic membranes and their "priming" for synaptic insertion and this results in elevated GluA1 synaptic incorporation 39 .…”

Pathway-specific dysregulation of striatal excitatory synapses by LRRK2 mutations

“…Similarly, the evidence of increased synaptic PKA activities was observed in +/RC and not +/GS striatal synaptic fractions. This increased PKA activity in the RC synapses is expected to positively correlate with elevations in dSPNs signaling ( Zhai et al, 2019 ). Specifically, phosphorylation of GluA1 at Ser 845 by PKA facilitates the targeting of the receptors to extrasynaptic membranes and their ‘priming’ for synaptic insertion and this results in elevated GluA1 synaptic incorporation ( Diering and Huganir, 2018 ).…”