Phosphodiesterase-10A changes in basal ganglia circuits in two mouse genetic models of DYT1 Dystonia.

DYT1 Dystonia is a movement disorder, caused by a 3-bp deletion in the torsinA gene, characterized by functional rather than structural abnormalities in basal ganglia. Phosphodiesterase-10A (PDE10A) is a key enzyme in the catabolism of cyclic nucleotides, that has peculiar distribution in the basal ganglia. Interestingly, in DYT1 transgenic mouse model overexpressing either human wild-type (hWT) or mutant torsinA (hMT) we have previously demonstrated changes in PDE10A expression and activity, which are opposite in the entopeduncular neucleus and external globus pallidus. We now intend to verify whether similar PDE10A changes could occur also in the basal ganglia of a DYT1 knock-in mouse model, in which the torsinA deletion is inserted in the endogenous gene (Tor1a+/Δgag). Immunohistochemical analysis was used for identification of PDE10A positive neurons and processes. Quantitative analysis of PDE10A expression was assessed by immunoblotting. PDE10A-dependent cAMP hydrolyzing activity was evaluated using [3H]-cAMP as substrate and papaverine, a well-known PDE10A-inhibitor, on tissue homogenates. Our studies demonstrate that PDE10A expression and activity were clearly increased in the globus pallidus of hMT and of Tor1a+/Δgag mice compared to controls. In the entopeduncular nucleus, PDE10A expression and activity were significantly decreased both in hWT and hMT mice, and basically reduced in Tor1a+/Δgag mice respect to wild type. Our findings show a differential expression of PDE10A in the direct and indirect pathway in both DYT1 models. We hypothesize that the 3bp deletion of torsinA may affect expression and/or axonal transport of PDE10A. ΔE-TorsinA could interfere with PDE10A trafficking with mechanisms that are still to be clarified.