title: Aberrant plasticity and "learned" motor inhibition in Parkinson's disease.
abstract: Parkinson's disease (PD) is a progressive neurodegenerative movement disorder characterized by severe loss of substantia nigra dopamine (DA) neurons. The target region of substantia nigra DA neurons is the dorsal striatum. According to the classic model, activation of DA receptors on striatal medium spiny neurons (MSNs) modulates their intrinsic excitability. Activation of D1 receptors makes MSNs in the direct "Go" pathway more excitable, whereas activation of D2 receptors makes MSNs in the indirect "NoGo" pathway less excitable. Therefore increased DA increases the responsiveness of the Go pathway while decreases the responsiveness of the NoGo pathway. Both mechanisms increase motor output. Conversely, diminished DA will favor the inhibitory NoGo pathway. Therefore, DA has direct, "on-line" effect on motor performance. However, in addition to modulating the intrinsic excitability of MSNs "on-line", DA also modulates corticostriatal plasticity, therefore could potentially produce cumulative and long-lasting changes in corticostriatal throughput. Studies in my lab suggest that DA blockade leads to both direct motor performance impairment and D2 receptor dependent NoGo learning ("learned" motor inhibition) that gradually deteriorates motor performance. NoGo learning is experience dependent and task specific. It is different from blocked learning since NoGo learning impairs future performance even after DA is restored. More recent data from my lab suggest that NoGo learning in the absence of DA arises from increased LTP at the indirect pathway corticostriatal synapses and contributes significantly to PD-like motor symptoms. Our data and hypotheses suggest a novel therapeutic strategy for PD that targets directly signaling molecules for corticostriatal plasticity (e.g. the cAMP pathway and downstream signaling molecules) and prevents aberrant plasticity under conditions of DA denervation.
authors.affiliation: Neurobiology Department, University of Chicago, Chicago, IL, USA. xzhuang@bsd.uchicago.edu
authors.forename: Xiao-Xi
authors.initials: XX
authors.lastname: Zhuang
mesh_terms: D003342:Corpus Striatum / Q000166:cytology; D004298:Dopamine / Q000502:physiology*; D059290:Dopaminergic Neurons / Q000473:pathology; D006801:Humans; D009473:Neuronal Plasticity; D010300:Parkinson Disease / Q000503:physiopathology*; D017447:Receptors, Dopamine D1 / Q000502:physiology; D017448:Receptors, Dopamine D2 / Q000502:physiology; D013378:Substantia Nigra / Q000473:pathology
chemical_list: D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D004298:Dopamine