Clinical and experimental data point to the basal ganglia network dysfunction as the main culprit in DYT1 dystonia pathophysiology. Our recent work showed, in the basal ganglia circuit of a transgenic DYT1 mouse model, an altered expression of the enzyme phosphodiesterase 10A (PDE10A). PDE10A is highly enriched in the GABAergic medium spiny projection neurons of the mammalian striatum, and reaches the basal ganglia output structures through the transport along the striatal projections. Here we want to study the expression of PDE10A and A2A receptor proteins, that are both involved in basal ganglia cyclic nucleotide pathway, in a Tor1a¿gag/+ mice dystonia model. Our approach will include immunohistochemistry, confocal microscopy, biochemistry, and physiology. We therefore propose to investigate the striatal output pathways in Tor1a¿gag/+ mice in order to characterize the alterations of the basal ganglia network in DYT1 dystonia. More importantly, we will test the effects of in vivo mouse pharmacological treatment in rescuing the alterations of basal ganglia activity.
Our laboratory was the first to investigate PDE10A distribution and expression in a mouse model of DYT1 dystonia. In our previous work (D¿Angelo et al., 2017), we utilized mice overexpressed human wild type (hWT) or mutant (hMT) torsinA (Sharma et al., 2005), in addition to endogenous murine wild type torsinA, that might give rise to abnormalities depending on overexpression itself (Grundmann et al., 2007). In this model, we found a differential, opposite regulation of PDE10A in the two striatal output pathways, with increased expression and enzymatic activity in striatopallidal pathway, and decreased in the striatoentopeduncular one. This differential expression could mirror the imbalance between the two pathways. Therefore, with the purpose of achieving knowledge advancement we aim at validating and extending these observations in a more recent DYT1 dystonia knock-in mouse model, which carries the same ¿gag mutation in torsinA that causes the human disease.