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Phosphodiesterase-10A opposite changes in striato-pallidal and striato-entopeduncular pathways of a transgenic mouse model of DYT1 Dystonia.

Research paper by V V D'Angelo, V V Castelli, M M Giorgi, S S Cardarelli, I I Saverioni, F F Palumbo, P P Bonsi, A A Pisani, C C Giampà, R R Sorge, S S Biagioni, F R FR Fusco, G G Sancesario

Indexed on: 25 Jan '17Published on: 25 Jan '17Published in: The Journal of neuroscience : the official journal of the Society for Neuroscience



Abstract

We report that changes of phosphodiesterase-10A (PDE10A) can map widespread 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 and cGMP, whose synthesis is stimulated by D1 and inhibited by D2 receptors, expressed in striato-entopeducuncular/substantia nigra or striato-pallidal pathways, respectively.PDE10A was studied in control mice (NT), and in mice carrying human wild-type torsinA (hWT) or mutant torsinA (hMT). Quantitative analysis of PDE10A expression was assessed in different brain areas by rabbit anti-PDE10A antibody immunohistochemistry and Western blotting. PDE10A-dependent cAMP hydrolyzing activity and PDE10A mRNA were also assessed. Striato-pallidal neurons were identified by rabbit anti-enkephalin antibody.In NT mice, PDE10A is equally expressed in medium spiny striatal neurons and in their projections to entopeduncular nucleus/substantia nigra and to external globus pallidus. In hMT, PDE10A content selectively increases in enkephalin positive striatal neuronal bodies; moreover, PDE10A expression and activity significantly increase in globus pallidus but decrease in entopeduncular nucleus/substantia nigra compared to NT. A similar trend in PDE10A changes is present in hWT, but such changes are not always significant. However, PDE10A mRNA expression appears comparable among NT, hWT and hMT.In DYT1 transgenic mice, the opposite changes of PDE10A in striato-entopeduncular/nigral projections, and in striato-pallidal projections might respectively lead at a time to an increased intensity and duration of D1 stimulated- and D2 inhibited-cAMP and -cGMP signaling pathways, determining an imbalance between direct and indirect pathways in focusing movements properly.In DYT1 transgenic mice model of dystonia, PDE10A, a key enzyme in cAMP and cGMP catabolism, is down regulated in striatal projections to entopeduncular nucleus/substantia nigra, preferentially expressing D1 receptors that stimulate cAMP/cGMP synthesis. Conversely, in DYT1 mice PDE10A is up-regulated in striatal projections to globus pallidus, preferentially expressing D2 receptors that inhibit cAMP/cGMP synthesis. The opposite changes of PDE10A in striato-entopeduncular/substantia nigra and striato-pallidal pathways might tightly interact downstream to dopamine receptors, likely determining at a time an increased intensity and duration respectively of D1 stimulated and D2 inhibited cAMP/cGMP signals. Therefore, PDE10A changes in DYT1 model of dystonia can portray the functional imbalance of basal ganglia circuits, affecting direct and indirect pathways simultaneously.

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