Loss of corticostriatal and thalamostriatal homeostasis in the direct and indirect pathways in mouse Parkinsonism

ESCANDE M.V.; TARAVINI I.; BELFORTE JE; MURER M.G.

Montpellier

Simposio; 12th Meeting of the French Neuroscience Society; 2015

Societe des neurosciences

It is widely accepted that an imbalance between the direct and indirect pathways underlies Parkinson?s disease symptoms, like the characteristic slowness of movement. However, no study has yet addressed whether activity in striatal medium spiny neurons (MSNs) projecting through the direct (dMSNs) and indirect (iMSNs) pathways correlates to symptom onset, symptom severity or degree of nigrostriatal degeneration in animal models of Parkinson?s disease. Nor whether it involves corticostriatal connections exclusively or also extends to thalamostriatal connectivity. In order to study responsiveness of both populations of MSNs to cortical and thalamic inputs in control and in different stages of nigrostriatal degeneration, we performed juxtacelular in vivo recordings in sham and 6-OHDA-treated Drd1a-tdTomato BAC transgenic mice under urethane anesthesia. We found that, contrary to the view that both pathways have similar gain in normal conditions, dMSNs respond more intensely to cortical inputs than iMSNs. Moreover, we also demonstrate that in asymptomatic mice with partial nigrostriatal degeneration, dMSNs present significant functional disconnection from motor cortex whereas iMSNs present no changes in their connectivity. Not only has the gain of the pathways turned upside-down, but also their timing, in symptomatic Parkinsonian mice, in which iMSNs fire significantly more and earlier than dMSNs. Altogether our data suggest that corticostriatal connectivity favors GO (direct pathway) over no-GO (indirect pathway) action signals in normal conditions. As nigrostriatal degeneration progresses GO signals are gradually disconnected, suggesting that homeostatic compensations are ineffective over the direct pathway, but clinical diagnosis remains elusive until the gain and timing of no-GO signals in the indirect pathway are also affected.