Striatal Dopaminergic Denervation and Spine Loss in MPTP-Treated Monkeys

Dopamine (DA) plays a critical role in regulating spine density on medium-sized spiny neurons (MSNs) in the striatum. Quantitative analysis of Golgi-impregnated MSNs in striatal sections at the level of the anterior commissure (commissural striatum) from MPTP-treated monkeys with complete DA denervation showed a significant reduction in spine density in both the caudate nucleus and putamen compared with that in controls. Similar analysis in partially DA-denervated striata revealed that the loss of spines was tightly correlated with the relative degree of dopamine depletion. Quantitative electron microscopy (EM) analyses showed a significant decrease in the density of both D1-immunolabeled and immunonegative spines in the commissural putamen of MPTP-treated monkeys, suggesting that DA depletion causes a reduction of spines on both direct and indirect pathway MSNs in the striatum of parkinsonian monkeys. Both the degree of striatal dopamine loss and extent of spine degeneration are correlated with low level of calbindin expression in striatal subregions, suggesting an important role of calcium in striatal pathogenesis of Parkinson's disease. This is further supported by electron microscopic data showing that calbindin-containing spines are less sensitive to degeneration in the caudate nucleus of partially depleted MPTP-treated monkeys. These findings provide strong evidence that striatal spine loss is an early sign of parkinsonism pathogenesis that is tightly correlated with the degree of striatal dopamine denervation and affects both direct and indirect striatofugal pathway neurons predominantly in calbindin-poor striatal subregions of MPTP-treated monkeys.