Dopaminergic modulation of striatal function and Parkinson’s disease
- 198 Downloads
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.
KeywordsParkinson’s disease Levodopa-induced dyskinesia Striatum Dopamine Synaptic plasticity Interneurons
This work was supported by grants from the JPB and IDP Foundations, USPHS (NS34696) and the Bumpus Foundation.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
- Alberico SL, Kim YC, Lence T, Narayanan NS (2017) Axial levodopa-induced dyskinesias and neuronal activity in the dorsal striatum. Neuroscience 343:240–249. https://doi.org/10.1016/j.neuroscience.2016.11.046 CrossRefPubMedGoogle Scholar
- Chalimoniuk M, Langfort J (2007) The effect of subchronic, intermittent L-DOPA treatment on neuronal nitric oxide synthase and soluble guanylyl cyclase expression and activity in the striatum and midbrain of normal and MPTP-treated mice. Neurochem Int 50:821–833. https://doi.org/10.1016/j.neuint.2007.02.002 CrossRefPubMedGoogle Scholar
- Dehorter N, Guigoni C, Lopez C, Hirsch J, Eusebio A, Ben-Ari Y, Hammond C (2009) Dopamine-deprived striatal GABAergic interneurons burst and generate repetitive gigantic IPSCs in medium spiny neurons. J Neurosci 29:7776–7787. https://doi.org/10.1523/JNEUROSCI.1527-09.2009 CrossRefPubMedGoogle Scholar
- Graybiel AM (2008) Habits, rituals, and the evaluative brain. Ann Rev Neurosci 31:359–387. https://doi.org/10.1146/annurev.neuro.29.051605.112851 CrossRefPubMedGoogle Scholar
- Kataoka Y, Kalanithi PS, Grantz H, Schwartz ML, Saper C, Leckman JF, Vaccarino FM (2010) Decreased number of parvalbumin and cholinergic interneurons in the striatum of individuals with Tourette syndrome. J Comp Neurol 518:277–291. https://doi.org/10.1002/cne.22206 CrossRefPubMedPubMedCentralGoogle Scholar
- Nelson AB, Kreitzer AC (2014) Reassessing models of basal ganglia function and dysfunction. Ann Rev Neurosci 37:117–135. https://doi.org/10.1146/annurev-neuro-071013-013916 CrossRefPubMedGoogle Scholar
- Rafalovich IV, Melendez AE, Plotkin JL, Tanimura A, Zhai S, Surmeier DJ (2015) Interneuronal nitric oxide signaling mediates post-synaptic long-term depression of striatal glutamatergic synapses. Cell Rep 13:1336–1342. https://doi.org/10.1016/j.celrep.2015.10.015 CrossRefPubMedPubMedCentralGoogle Scholar
- Sammut S, Dec A, Mitchell D, Linardakis J, Ortiguela M, West AR (2006) Phasic dopaminergic transmission increases NO efflux in the rat dorsal striatum via a neuronal NOS and a dopamine D(1/5) receptor-dependent mechanism. Neuropsychopharmacology 31:493–505. https://doi.org/10.1038/sj.npp.1300826 CrossRefPubMedGoogle Scholar
- Suarez LM, Solis O, Carames JM, Taravini IR, Solis JM, Murer MG, Moratalla R (2014) L-DOPA treatment selectively restores spine density in dopamine receptor D2-expressing projection neurons in dyskinetic mice. Biol Psychiatry 75:711–722. https://doi.org/10.1016/j.biopsych.2013.05.006 CrossRefPubMedGoogle Scholar
- Suarez LM, Alberquilla S, Garcia-Montes JR, Moratalla R (2018) Differential synaptic remodeling by dopamine in direct and indirect striatal projection neurons in Pitx3(−/−) mice, a genetic model of Parkinson’s disease. J Neurosci 38:3619–3630. https://doi.org/10.1523/JNEUROSCI.3184-17.2018 CrossRefPubMedGoogle Scholar
- Xu M, Li L, Pittenger C (2016) Ablation of fast-spiking interneurons in the dorsal striatum, recapitulating abnormalities seen post-mortem in Tourette syndrome produces anxiety elevated grooming. Neuroscience 324:321–329. https://doi.org/10.1016/j.neuroscience.2016.02.074 CrossRefPubMedPubMedCentralGoogle Scholar