PDE10A is up-regulated in Enkephalin striatal projection neurons of a transgenic mouse model of DYT1 Dystonia

Introduction - Phosphodiesterase-10A (PDE10A), a key enzyme in the catabolism of cAMP in the striatum, is increased in some striatal neurons but decreased in others, throughout the dorsolateral striatum in a transgenic mouse model of DYT1 Dystonia (hMT). We hypothesized that PDE10A either increases or decreases selectively in specific populations of striatal neurons of hMT mice. We undertook a double labelling immunohistochemical study of PDE10A and enkephalin (Enk)-containing neurons, which project to the lateral segment of GP giving rise to the “indirect” pathway. Methods - Free floating sections of the striatum were incubated with a PDE10A mouse monoclonal antibody, and with rabbit anti-Leucine-Enk and rabbit anti Met-Enk. Sections were subsequently incubated with goat anti rabbit cyanine Cy™2- and goat anti mouse cyanine Cy™3-conjugated secondary antibody. Results - In control mice, PDE10A immunofluorescence was observed in the vast majority of the striatal neurons with similar intensity in the cell bodies and in the neuropil. Moreover, some cell bodies were expressing a faint ENK immunofluorescence throughout the striatum, colocalizing in PDE10A positive neurons. In hMT mice, some striatal neurons were expressing ENK immunofluorescence; moreover, PDE10A immunofluorescence appeared intense in some neurons, but low in other adjacent neurons throughout the striatum. The subpopulation of striatal neurons expressing up-regulation of PDE10A in hMT mice showed complete overlap with cell bodies expressing ENK immunofluorescences. Conversely, the neurons labelled with low PDE10A immunoreactivity were completely devoid of the ENK immunoreactivity. Conclusions - Our data demonstrate opposite changes of PDE10A expression in ENK positive and ENK negative striatal neurons of hMT mice. We can speculate that such PDE10A changes in the striatum can map widespread functional impairment of striatal projections, differentially affecting the direct and indirect pathway in basal ganglia circuits of hMT mice.