Phosphodiesterase-10A inverse changes in striatopallidal and striatoentopeduncular pathways of a transgenic mouse model of DYT1 dystonia

In most forms of dystonia, brain regions have functional rather than structural abnormalities. We report that changes of phosphodiesterase-10A (PDE10A) can map functional imbalance of basal ganglia circuits in a mouse model of DYT1 dystonia overexpressing mutant torsinA. PDE10A is a key enzyme in the catabolism of second messenger cAMP/cGMP, whose synthesis is stimulated by D1 or inhibited by D2 receptors, expressed in striatoentopeducuncular or striatopallidal pathways respectively. PDE10A was studied in control mice and in mice carrying either human wild-type torsinA or mutant torsinA. Quantitative analysis of PDE10A expression in different brain areas was assessed by rabbit anti-PDE10A antibody immunohistochemistry and Western blotting. PDE10A dependent cAMP hydrolyzing activity and PDE10A mRNA were also assessed. In control mice, PDE10A has unique distribution in basal ganglia, equally expressed in medium spiny neurons in the striatum and in their projections to entopeduncular nucleus and external globus pallidus. In mice carrying mutant torsinA, morphological and biochemical studies show that PDE10A expression and activity are significantly decreased in the entopeduncular nucleus, but clearly increased in the globus pallidus compared to control mice. A similar trend of PDE10A changes is present in wild type torsinA mice, but such changes are not always significant. However, PDE10A mRNA expression appears comparable among the three animal groups. In DYT1 transgenic mice, PDE10A down-regulation in striatoentopeduncular projections might lead to potentiating of D1 stimulation of cAMP/cGMP signals, while PDE10A up-regulation in striatopallidal projections might lead to potentiating of D2 inhibition of cAMP/cGMP signals, facilitating both pathways to induce motor activity.