VMAT2-Deficient Mice Display Nigral and Extranigral Pathology and Motor and Nonmotor Symptoms of Parkinson's Disease

Figure 2

Timeline of Parkinsonian features observed in the VMAT2-deficient mice from 2–30 months of age. Symptoms or pathology indicated by a solid colored box did not increase in severity as the mice aged. All boxes end at the last age the symptom or pathology was measured. Behavioral phenotypes: reductions in locomotor activity and latency to behavioral signs of sleep were first observed at 2 months of age and were found to persist until their last measurements at 6 months of age and 18 months of age, respectively. Gastric emptying was first measured at 2 months of age, and increased in severity until the last time point at 18 months of age. Hyposmia began at 4 months, with full anosmia at 6 months of age and persisting until the last evaluation at 18 months. Anxiety-like behavior was first assessed at 4 months of age, persisting until 6 months of age. Even though depressive-like behaviors were measured at 4–6 months of age, presence of a depressive-like phenotype was not detected until 12 months of age, lasting until 15 months of age. Finally, reductions in forepaw stride length were not seen until 27 months, reaching full severity at 30 months of age. Neurochemical pathology: evidence of oxidative damage was first observed through the formation of cysteinyl adducts at 2 months, which were still present at 12 months. Protein carbonyls and 3-nitrotyrosine formation did not occur until 12 months of age. Accumulation of α-synuclein began at 18 months with evidence remaining until 24 months of age. Loss of striatal DAT expression measured immunohistochemically began at 6 months of age progressing in severity until 22 months of age. Reductions in striatal TH expression begin at 18 months of age, reaching maximal severity at 30 months. Degeneration of the LC starts at 12 months of age in the VMAT2-deficient animals, preceding nigral loss, which does not begin until 18 months of age.