There is a decline in DAT binding that defines a threshold for early Parkinsonism (Guttman et al. 1997) making it possible to follow disease progression in PD patients (Nurmi et al. 2000; Marek et al. 2001; Winogrodzka et al. 2001). DAT binding aids in the early diagnosis of PD from other motor disorders helping to detect patients at baseline who after follow-up months or years later show no change

in status (Jennings et al. 2004; Marshall et al. 2009). In addition, as compensation for the decrease in DA terminals, there is down-regulation of DAT protein helping Inhibitors,research,lifescience,medical promote higher sustained levels of DA in the synaptic cleft (Lee et al. 2000). Could there be a compensatory increase in DAT in presymptomatic PD? Compensation could occur by sprouting new terminals or by increasing DAT protein expression in surviving nerve terminals. Several studies in rodents have reported selective lesions to the Inhibitors,research,lifescience,medical DA innervation

of the dorsal striatum are accompanied by sprouting of healthy neurons surrounding the site of injury (Dravid et al. 1984; Blanchard et al. 1996; Batchelor et al. 1999; Bezard et al. 2000). However, this is unlikely in this rotenone microsphere model as TH staining, an indirect measure of DA terminals in the dorsal striatum is significantly reduced. It is more plausible to assume an increase in DAT protein, Inhibitors,research,lifescience,medical a possibility raised by learn more Bellucci and coworkers (2011) working with 12-month-old SYN120 transgenic mice expressing a truncated human α-synuclein. These mice show an age-dependent increase in α-synuclein deposition in the soma and dendrites of DA neurons of the SN and increased numbers of activated microglia in the surrounding tissue (Tofaris et al. 2006). While there is no decrease in the number of TH positive neurons in the substantia nigra there is Inhibitors,research,lifescience,medical a 30% decrease in DA levels and reduced

DA release in the dorsal striatum (Tofaris et al. 2006; Garcia-Reitbock et al. 2010). The behavioral phenotype presents with reduced locomotion at 12–18 months of age as compared to age-matched controls, but there are no signs and symptoms of Parkinsonism (Tofaris Inhibitors,research,lifescience,medical et al. 2006; Bellucci et al. 2011). These mice show complexes of DAT/α-synuclein clustering in the cytosol of DA fibers in the striatum that accumulate MTMR9 with age as compared to controls (Bellucci et al. 2011). These changes are accompanied by a significant increase of DAT protein (Bellucci et al. 2011). There is a direct protein–protein interaction between α-synuclein and DAT that is thought to function as a negative regulator of DA neurotransmission (Wersinger and Sidhu 2003; Eriksen et al. 2010; Swant et al. 2011). The gradual and subthreshold loss of DA function in the striatum of these SYN120 transgenic mice, together with the accumulation of α-synuclein aggregates, increase in DAT levels, and tissue neuroinflammation, without motor signs of PD have many similarities with the rotenone microsphere model described here.