title: Phosphodiesterase-10A Inverse Changes in Striatopallidal and Striatoentopeduncular Pathways of a Transgenic Mouse Model ofDYT1Dystonia.
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 receptors and inhibited by D2 receptors preferentially expressed in striatoentopeducuncular/substantia nigra or striatopallidal 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. Striatopallidal 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 mice, PDE10A content selectively increases in enkephalin-positive striatal neuronal bodies; moreover, PDE10A expression and activity in hMT mice, compared with NT mice, significantly increase in globus pallidus but decrease in entopeduncular nucleus/substantia nigra. Similar changes of PDE10A occur in hWT mice, but such changes are not always significant. However, PDE10A mRNA expression appears comparable among NT, hWT, and hMT mice.InDYT1transgenic mice, the inverse changes of PDE10A in striatoentopeduncular and striatopallidal projections might result over time in an imbalance between direct and indirect pathways for properly focusing movement. The decrease of PDE10A in the striatoentopeduncular/nigral projections might lead to increased intensity and duration of D1-stimulated cAMP/cGMP signaling; conversely, the increase of PDE10A in the striatopallidal projections might lead to increased intensity and duration of D2-inhibited cAMP/cGMP signaling.SIGNIFICANCE STATEMENTInDYT1transgenic mouse model of dystonia, PDE10A, a key enzyme in cAMP and cGMP catabolism, is downregulated in striatal projections to entopeduncular nucleus/substantia nigra, preferentially expressing D1 receptors that stimulate cAMP/cGMP synthesis. Conversely, inDYT1mice, PDE10A is upregulated in striatal projections to globus pallidus, preferentially expressing D2 receptors that inhibit cAMP/cGMP synthesis. The inverse changes to PDE10A in striatoentopeduncular/substantia nigra and striatopallidal pathways might tightly interact downstream to dopamine receptors, likely resulting over time to increased intensity and duration respectively of D1-stimulated and D2-inhibited cAMP/cGMP signals. Therefore, PDE10A changes in the DYT1 model of dystonia can upset the functional balance of basal ganglia circuits, affecting direct and indirect pathways simultaneously.
authors.affiliation: Department of Systems Medicine, Tor Vergata University of Rome, 00133 Rome, Italy.
authors.forename: Vincenza
authors.initials: V
authors.lastname: D'Angelo
authors.affiliation: Department of Biology and Biotechnology "Charles Darwin," Sapienza University of Rome, 00185 Rome, Italy, and.
authors.forename: Valentina
authors.initials: V
authors.lastname: Castelli
authors.affiliation: Department of Biology and Biotechnology "Charles Darwin," Sapienza University of Rome, 00185 Rome, Italy, and.
authors.forename: Mauro
authors.initials: M
authors.lastname: Giorgi
authors.affiliation: Department of Biology and Biotechnology "Charles Darwin," Sapienza University of Rome, 00185 Rome, Italy, and.
authors.forename: Silvia
authors.initials: S
authors.lastname: Cardarelli
authors.affiliation: Department of Biology and Biotechnology "Charles Darwin," Sapienza University of Rome, 00185 Rome, Italy, and.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Saverioni
authors.affiliation: Department of Systems Medicine, Tor Vergata University of Rome, 00133 Rome, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Palumbo
authors.affiliation: Santa Lucia Foundation, 00179 Rome, Italy.
authors.forename: Paola
authors.identifier: 0000-0001-5940-9028
authors.initials: P
authors.lastname: Bonsi
authors.affiliation: Department of Systems Medicine, Tor Vergata University of Rome, 00133 Rome, Italy.|Santa Lucia Foundation, 00179 Rome, Italy.
authors.forename: Antonio
authors.identifier: 0000-0002-8432-594X
authors.initials: A
authors.lastname: Pisani
authors.affiliation: Santa Lucia Foundation, 00179 Rome, Italy.
authors.forename: Carmela
authors.initials: C
authors.lastname: Giampà
authors.affiliation: Department of Systems Medicine, Tor Vergata University of Rome, 00133 Rome, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Sorge
authors.affiliation: Department of Biology and Biotechnology "Charles Darwin," Sapienza University of Rome, 00185 Rome, Italy, and.
authors.forename: Stefano
authors.identifier: 0000-0003-1544-3907
authors.initials: S
authors.lastname: Biagioni
authors.affiliation: Santa Lucia Foundation, 00179 Rome, Italy.
authors.forename: Francesca R
authors.initials: FR
authors.lastname: Fusco
authors.affiliation: Department of Systems Medicine, Tor Vergata University of Rome, 00133 Rome, Italy, sancesario@med.uniroma2.it.
authors.forename: Giuseppe
authors.identifier: 0000-0002-1772-9012
authors.initials: G
authors.lastname: Sancesario
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D004195:Disease Models, Animal; D004421:Dystonia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004745:Enkephalins / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018832:Molecular Chaperones / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D009415:Nerve Net / Q000378:metabolism / Q000473:pathology; D009434:Neural Pathways / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D010208:Papaverine / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D013378:Substantia Nigra / Q000378:metabolism*
chemical_list: D004745:Enkephalins; D018832:Molecular Chaperones; D010726:Phosphodiesterase Inhibitors; D012333:RNA, Messenger; C108175:TOR1A protein, human; D010208:Papaverine; D000242:Cyclic AMP; C119843:PDE10A protein, human; D010727:Phosphoric Diester Hydrolases
keywords: PDE10A; basal ganglia; cAMP; dopamine receptors; dystonia; hyperkinetic disorder