Loss of homeostasis in the direct pathway in a mouse model of asymptomatic Parkinson´s disease

ESCANDE MV; TARAVINI IRE; ZOLD CL; BELFORTE J; MURER MG

JOURNAL OF NEUROSCIENCE

SOC NEUROSCIENCE

Lugar: Washington; Año: 2016 vol. 36 p. 5686 - 5698

0270-6474

The characteristic slowness of movement of Parkinson?s disease relates to an imbalance in the activity of striatal medium spiny neurons of the direct (dMSNs) and indirect (iMSNs) pathways. However, it is still unclear if 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 two 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. Thus, 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.