The in vivo imaging model we have developed measures fluorescently-labeled a-synuclein in individual expressing neuronal cell bodies and presynaptic terminals and can follow them serially over a period of months. It must of course be noted that Syn-GFP may have different biophysical properties than untagged asynuclein, including an alteration in propensity to aggregate. Recent studies suggest that split fluorescent protein a-synuclein constructs are able to form oligomeric and larger species but the similarity of these aggregates to those found in PD and other synucleinopathies is not clear. Although more work needs to be done to compare fibrillization kinetics and other biophysical properties of GFP-tagged a-synuclein to the untagged species, the use of in vivo imaging in Syn-GFP mice represents a substantial technical advance that can be used to address many questions relating to a-synuclein biology in a relevant context. Our data show that in this transgenic line a sparse subset of cortical neurons expresses Syn-GFP and that the density of expressing neurons does not change substantially with age. In addition, chronic imaging reveals that the subset of Syn-GFP expressing cells seems to be invariant over the course of months, since the rates at which new neurons start to express Syn-GFP or already expressing ones stop expressing the transgene both appear to be negligible at the ages tested. In addition, the placement of the cranial window itself does not appear to cause detectable changes in Syn-GFP expression. These results suggest that this model system would be particularly useful for experiments that follow asynuclein expression in individual neurons and synapses over time, both before and after NCB-0846 particular manipulations. One possible application for these techniques would be to test the role of different biochemical pathways in determining steady-state asynuclein levels in vivo both in the cell body and at the presynaptic terminal. Pharmacologic or genetic manipulation can first be targeted to specific processes thought to be important for asynuclein regulation and toxicity such as the ubiquitin-proteasome system, Olodaterol autophagy or a-synuclein phosphorylation.