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

Vincenza D’Angelo, Valentina Castelli, Mauro Giorgi, Silvia Cardarelli, Ilaria Saverioni, Francesca Palumbo, Paola Bonsi, Antonio Pisani, Carmela Giampà, Roberto Sorge, Stefano Biagioni, Francesca R. Fusco, Giuseppe Sancesario

Research output: Contribution to journalArticle

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-dependentcAMPhydrolyzing 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 ofPDE10Ain striatoentopeduncularandstriatopallidal projectionsmightresult over time inan 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.

Original languageEnglish
Pages (from-to)2112-2124
Number of pages13
JournalJournal of Neuroscience
Volume37
Issue number8
DOIs
Publication statusPublished - Feb 22 2017

Keywords

  • Basal ganglia
  • CAMP
  • Dopamine receptors
  • Dystonia
  • Hyperkinetic disorder
  • PDE10A

ASJC Scopus subject areas

  • Neuroscience(all)

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  • Cite this

    D’Angelo, V., Castelli, V., Giorgi, M., Cardarelli, S., Saverioni, I., Palumbo, F., Bonsi, P., Pisani, A., Giampà, C., Sorge, R., Biagioni, S., Fusco, F. R., & Sancesario, G. (2017). Phosphodiesterase-10A inverse changes in striatopallidal and striatoentopeduncular pathways of a transgenic mouse model of DYT1 dystonia. Journal of Neuroscience, 37(8), 2112-2124. https://doi.org/10.1523/JNEUROSCI.3207-15.2016