Altered cortical and thalamic connectivity in the direct and indirect pathways in hemiparkinsonian Drd1a-tdTomato BACtransgenic mice.

ESCANDE MV; TARAVINI IRE; BELFORTE J; MURER MG

Congreso; 17th International Congress of Parkinson’s Disease and Movement Disorders; 2013

Movement Disorders

Objective: To determine the gain of the connectivity between striatal medium spiny neurons (MSN) from the direct and indirect pathways and their main glutamatergic inputs in different stages of dopaminergic depletion in vivo.  Background: Physiological studies support the proposition that following dopamine depletion the excitability of the direct and indirect pathways of the basal ganglia moves in opposite directions. Although it is assumed that this imbalance plays a critical role in Parkinson´s disease symptoms, new technological approaches such as transgenic mice allowing the identification of D1-MSNs and D2-MSNs combined with in vivo juxtacellular labelling, have not been used to tackle this issue.   Methods: Three weeks after 6-OHDA injection mice were tested in an accelerated rotarod. One week later we performed in vivo juxtacellular recordings to study responses of MSNs to frontal cortex and thalamic stimulation in control, partially and fully dopamine depleted mice under anaesthesia. Experiments were performed in Drd1a-tdTomato BAC transgenic mice. After being recorded, neurons were labeled with neurobiotin and revealed with a green fluorescent marker.  Results: In sham mice, D1-MSNs (n= 11) and putative D2-MSNs (n=9) show no difference in their responsiveness to cortical stimulation (ANOVA p= 0.1127). Putative D2 MSNs showed a highly increase responsiveness in severely depleted mice (n=7) (1.74 versus 1.02 spikes per stimulation trial in sham mice; ANOVA p=0.0019). Conversely, D1-MSNs (n=5) did not respond at 600 µA in severe dopamine depleted mice and only show a modest response at 900 µA (0.55 spikes per trial), whereas sham D1-MSNs show a maximal response at 600 µA (1.03 spikes per trial)..Thalamic stimulation evokes similar responses in all groups (ANOVA p=0.6391). Mice with partial nigrostriatal lesion show intermediate changes.  Conclusions: This first report on the in vivo activity of identified D1- and D2-MSNs in the mouse shows that D2-MSNs’ responsiveness to cortical stimulation is increased and D1-MSNs responsiveness decreased after severe nigrostriatal degeneration as predicted by basal ganglia models. In contrast, MSN are capable of responding to thalamic stimulation even in a severe dopamine depleted state. Drd1a-Tomato transgenic mouse are well suited to differentially study medium spiny projection neurons in vivo.