Altered cortical but not thalamic connectivity in the direct and indirect pathways in hemiparkinsonian Drd1a-tdTomato BACtransgenic mice.

ESCANDE M; TARAVINI IRE; BELFORTE J; MURER MG

Sydney

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

Movement Disorder Society.

Objective: To determine the gain of the connectivity betweenstriatal medium spiny neurons (MSN) from the direct and indirectpathways and their main glutamatergic inputs in different stages ofdopaminergic depletion in vivo.Background: Physiological studies support the proposition thatafter dopamine depletion the excitability of direct and indirect pathwaysof the basal ganglia changes in opposite directions. Although itis assumed that this imbalance plays a critical role in Parkinson?sdisease symptoms, new technological approaches such as transgenicmice allowing the identification of D1-MSNs and D2-MSNs combinedwith in vivo juxtacellular labelling, have not been used totackle this issue.Methods: After 6-OHDA lesion mice were tested in an acceleratingrotarod. One week later we performed in vivo juxtacellularrecordings to study responses of MSNs to frontal cortex and thalamicstimulation in control, partially and fully dopamine depleted Drd1atdTomatoBAC transgenic mice, under anaesthesia. After beingrecorded, neurons were labeled with neurobiotin.Results: In sham mice, D1-MSNs (n 5 11) and putative D2-MSNs (n 5 9) show no difference in their responsiveness to corticalstimulation (ANOVA p 5 0.1127). Putative D2-MSNs showed ahighly increased responsiveness in severely depleted mice (n 5 7)(1.8 6 0.3 versus 0.7 6 0.2 spikes per stimulation trial in shammice; ANOVA p 5 0.0019). Conversely, D1-MSNs (n 5 5) did notrespond at 500 mA in severe dopamine depleted mice and only showa modest response at 900 mA (0.55 spikes/trial), whereas sham D1-MSNs show a maximal response at 500 mA (0.9 6 0.2 spikes/trial).Thalamic stimulation evokes similar responses in all groups(ANOVA p 5 0.6391). Mice with partial nigrostriatal lesion showintermediate changes.Conclusions: This first report on the in vivo activity of identifiedD1-and D2-MSNs shows that D2-MSNs? responsiveness to corticalstimulation is increased and D1-MSNs responsiveness decreased aftersevere nigrostriatal degeneration as predicted by basal ganglia models.In contrast, MSNs retained their normal response to thalamicstimulation even in a severe dopamine depleted state. Drd1a-Tomatotransgenic mouse are well suited to differentially study MSNs invivo.