Parkinson's disease (PD) is a common neurological disorder that primarily impairs the basal ganglia motor control circuit. It is caused by degeneration of midbrain dopamine neurons, particularly those in the substantia nigra (SN). The SN has two distinct components: SN pars compacta (SNc) and SN pars reticulata (SNr). The SNc contains the majority of nigrostriatal dopamine projection neurons that are compromised in PD. The SNr is a key output nucleus of the basal ganglia and the majority of its neurons are inhibitory 3-aminobutyric acid (GABA)-containing projection neurons that fire high frequency spikes that are often abnormal in PD. Past research has elucidated many important aspects of basal ganglia physiology and the pathophysiology of PD. However, many critical issues remain unanswered and many important motor abnormalities in PD can not be adequately explained with our current knowledge. NIH's Parkinson's Disease Research Agenda states that """"""""One poorly understood area concerns the consequences of dopamine loss outside the striatum"""""""". This application focuses precisely on these poorly understood areas. We hypothesize and our high quality preliminary data support that dendritically released dopamine from nigral dopamine neurons may directly act on SNr GABA output neurons. This ultra-short SNc-SNr dopamine pathway (comparing with the long distance nigro-striato-nigral loop) may provide a fast, direct dopamine control over this key basal ganglia output nucleus. Particularly, a tonic dopamine D1/D5 receptor-mediated direct excitation may aid in SNr GABA output neuron depolarization and regular firing pattern. Loss of this direct dopamine influence after dopamine neuron degeneration may contribute to the abnormalities in SNr GABA output neuron activity in parkinsonian brain and motor deficits. We have designed experiments to test our hypotheses. Multiple state-of-the-art approaches will be used, including single cell reverse transcription (RT)-PCR, quantitative electrophysiology, neurochemistry, neuropharmacology, and immunohistochemistry. Genetically modified mouse lines will also be used to aid in the experiments. New knowledge gained from the proposed projects will advance our understanding of the basal ganglia motor control circuit and the pathophysiology of PD and provide a potential route for therapeutic intervention in movement disorders of basal ganglia origin such as PD. The Public Health Relevance: Parkinson's disease is a common neurological disorder of the basal ganglia motor control neuronal circuit. Using an array of advanced techniques, the proposed experiments seek to delineate a novel, important dopamine pathway that directly influences a key basal ganglia output nucleus. The results will advance our understanding of the pathophysiology of Parkinson's disease and provide a potential route for therapeutic intervention in movement disorders of basal ganglia origin such as Parkinson's disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS058850-05
Application #
8330268
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Sutherland, Margaret L
Project Start
2008-09-01
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2014-08-31
Support Year
5
Fiscal Year
2012
Total Cost
$269,231
Indirect Cost
$87,318
Name
University of Tennessee Health Science Center
Department
Pharmacology
Type
Schools of Medicine
DUNS #
941884009
City
Memphis
State
TN
Country
United States
Zip Code
38163
Ding, Shengyuan; Li, Li; Zhou, Fu-Ming (2015) Nigral dopamine loss induces a global upregulation of presynaptic dopamine D1 receptor facilitation of the striatonigral GABAergic output. J Neurophysiol 113:1697-711
Ding, Shengyuan; Li, Li; Zhou, Fu-Ming (2015) Robust presynaptic serotonin 5-HT(1B) receptor inhibition of the striatonigral output and its sensitization by chronic fluoxetine treatment. J Neurophysiol 113:3397-409
Li, Li; Sagot, Ben; Zhou, Fu-Ming (2015) Similar L-dopa-stimulated motor activity in mice with adult-onset 6-hydroxydopamine-induced symmetric dopamine denervation and in transcription factor Pitx3 null mice with perinatal-onset symmetric dopamine denervation. Brain Res 1615:12-21
Ding, Shengyuan; Zhou, Fu-Ming (2014) Serotonin regulation of subthalamic neurons. Rev Neurosci 25:605-19
Theuns, Jessie; Verstraeten, Aline; Sleegers, Kristel et al. (2014) Global investigation and meta-analysis of the C9orf72 (G4C2)n repeat in Parkinson disease. Neurology 83:1906-13
Ding, Shengyuan; Li, Li; Zhou, Fu-Ming (2013) Presynaptic serotonergic gating of the subthalamonigral glutamatergic projection. J Neurosci 33:4875-85
Li, L; Zhou, F-M (2013) Parallel dopamine D1 receptor activity dependence of l-Dopa-induced normal movement and dyskinesia in mice. Neuroscience 236:66-76
Li, Li; Qiu, Guozhen; Ding, Shengyuan et al. (2013) Serotonin hyperinnervation and upregulated 5-HT2A receptor expression and motor-stimulating function in nigrostriatal dopamine-deficient Pitx3 mutant mice. Brain Res 1491:236-50
Wei, Wei; Li, Li; Yu, Guoliang et al. (2013) Supersensitive presynaptic dopamine D2 receptor inhibition of the striatopallidal projection in nigrostriatal dopamine-deficient mice. J Neurophysiol 110:2203-16
LeDoux, Mark S (2012) Exome sequencing for gene discovery: time does not stand still. Ann Neurol 72:628-9

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