title: Loss of Homeostasis in the Direct Pathway in a Mouse Model of Asymptomatic Parkinson's Disease.
abstract: The characteristic slowness of movement in Parkinson's disease relates to an imbalance in the activity of striatal medium spiny neurons (MSNs) of the direct (dMSNs) and indirect (iMSNs) pathways. However, it is still unclear whether this imbalance emerges during the asymptomatic phase of the disease or if it correlates with symptom severity. Here, we have used in vivo juxtacellular recordings and transgenic mice showing MSN-type-specific expression of fluorescent proteins to examine striatal imbalance after lesioning dopaminergic neurons of the substantia nigra. Multivariate clustering analysis of behavioral data discriminated 2 groups of dopamine-lesioned mice: asymptomatic (42 ± 7% dopaminergic neuron loss) and symptomatic (85 ± 5% cell loss). Contrary to the view that both pathways have similar gain in control conditions, dMSNs respond more intensely than iMSNs to cortical inputs in control animals. Importantly, asymptomatic mice show significant functional disconnection of dMSNs from motor cortex without changes in iMSN connectivity. Moreover, not only the gain but also the timing of the pathways is altered in symptomatic parkinsonism, where iMSNs fire significantly more and earlier than dMSNs. Therefore, cortical drive to dMSNs decreases after partial nigrostriatal lesions producing no behavioral impairment, but additional alterations in the gain and timing of iMSNs characterize symptomatic rodent parkinsonism.
  
  
  
  Prevailing models of Parkinson's disease state that motor symptoms arise from an imbalance in the activity of medium spiny neurons (MSNs) from the direct (dMSNs) and indirect (iMSNs) pathways. Therefore, it is hypothesized that symptom severity and the magnitude of this imbalanced activity are correlated. Using a mouse model of Parkinson's disease, we found that behaviorally undetectable nigrostriatal lesions induced a significant disconnection of dMSNs from the motor cortex. In contrast, iMSNs show an increased connectivity with the motor cortex, but only after a severe dopaminergic lesion associated with an evident parkinsonian syndrome. Overall, our data suggest that the lack of symptoms after a partial dopaminergic lesion is not due to compensatory mechanisms maintaining the activity of both striatal pathways balanced.
authors.affiliation: Systems Neuroscience Group, IFIBIO Bernardo Houssay, CONICET and Universidad de Buenos Aires, Department of Physiology and Biophysics, University of Buenos Aires School of Medicine, Buenos Aires, Argentina 1121, mvescande@gmail.com.
authors.forename: Mariela V
authors.initials: MV
authors.lastname: Escande
authors.affiliation: Experimental Parkinsonism Group, ININFA, CONICET, and University of Buenos Aires, Buenos Aires, Argentina 1121, and Experimental Neurobiology Laboratory, University of Entre Ríos, Concepción del Uruguay, Entre Ríos, Argentina 2820.
authors.forename: Irene R E
authors.initials: IR
authors.lastname: Taravini
authors.affiliation: Systems Neuroscience Group, IFIBIO Bernardo Houssay, CONICET and Universidad de Buenos Aires, Department of Physiology and Biophysics, University of Buenos Aires School of Medicine, Buenos Aires, Argentina 1121.
authors.forename: Camila L
authors.initials: CL
authors.lastname: Zold
authors.affiliation: Systems Neuroscience Group, IFIBIO Bernardo Houssay, CONICET and Universidad de Buenos Aires, Department of Physiology and Biophysics, University of Buenos Aires School of Medicine, Buenos Aires, Argentina 1121.
authors.forename: Juan E
authors.identifier: 0000-0002-6300-5314
authors.initials: JE
authors.lastname: Belforte
authors.affiliation: Systems Neuroscience Group, IFIBIO Bernardo Houssay, CONICET and Universidad de Buenos Aires, Department of Physiology and Biophysics, University of Buenos Aires School of Medicine, Buenos Aires, Argentina 1121.
authors.forename: M Gustavo
authors.initials: MG
authors.lastname: Murer
mesh_terms: D000818:Animals; D058070:Asymptomatic Diseases; D001931:Brain Mapping; D003342:Corpus Striatum / Q000503:physiopathology*; D059290:Dopaminergic Neurons / Q000378:metabolism; D005260:Female; D006706:Homeostasis; D051379:Mice; D008822:Mice, Transgenic; D009044:Motor Cortex / Q000503:physiopathology*; D009434:Neural Pathways / Q000503:physiopathology; D020734:Parkinsonian Disorders / Q000503:physiopathology*; D013378:Substantia Nigra / Q000503:physiopathology*
keywords: 6-OHDA; functional connectivity; in vivo electrophysiology; medium spiny neurons; striatum