title: Preservation of function in Parkinson's disease: what's learning got to do with it?
abstract: Dopamine denervation gives rise to abnormal corticostriatal plasticity; however, its role in the symptoms and progression of Parkinson's disease (PD) has not been articulated or incorporated into current clinical models. The 'integrative selective gain' framework proposed here integrates dopaminergic mechanisms known to modulate basal ganglia throughput into a single conceptual framework: (1) synaptic weights, the neural instantiation of accumulated experience and skill modulated by dopamine-dependent plasticity and (2) system gain, the operating parameters of the basal ganglia, modulated by dopamine's on-line effects on cell excitability, glutamatergic transmission and the balance between facilitatory and inhibitory pathways. Within this framework and based on recent work, a hypothesis is presented that prior synaptic weights and established skills can facilitate motor performance and preserve function despite diminished dopamine; however, dopamine denervation induces aberrant corticostriatal plasticity that degrades established synaptic weights and replaces them with inappropriate, inhibitory learning that inverts the function of the basal ganglia resulting in 'anti-optimization' of motor performance. Consequently, mitigating aberrant corticostriatal plasticity represents an important therapeutic objective, as reflected in the long-duration response to levodopa, reinterpreted here as the correction of aberrant learning. It is proposed that viewing aberrant corticostriatal plasticity and learning as a provisional endophenotype of PD would facilitate investigation of this hypothesis.
authors: Department of Neurobiology, The University of Chicago, Chicago, IL, USA. jabeeler@uchicago.edu
authors: Jeff A
authors: JA
authors: Beeler
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology; D001479:Basal Ganglia / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D010300:Parkinson Disease / Q000188:drug therapy / Q000473:pathology* / Q000503:physiopathology*
chemical_list: D000978:Antiparkinson Agents; D004298:Dopamine