Developmental changes in dendritic spine morphology in the striatum and their alteration in an A53T α-synuclein transgenic mouse model of Parkinson's disease.

The aging process is accompanied by various neurophysiological changes, and the severity of neurodegenerative disorders such as Parkinson's disease increases with aging. However, the precise neuroanatomical changes that accompany the aging process in both normal and pathological conditions remain unknown. This is in part because there is a lack of high-resolution imaging tool that has the capacity to image a desired volume of neurons in a high-throughput and automated manner. In the present study, focused ion beam/scanning electron microscopy (FIB/SEM) was used to image striatal neuropil in both wild-type (WT) mice and an A53T bacterial artificial chromosome human α-synuclein (A53T-BAC-) transgenic mouse model of Parkinson's disease, at 1 month, 3 months, 6 months, and 22 months of age. We demonstrated that spine density gradually decreases, and average spine head volume gradually increases with age in WT mice; suggesting a homeostatic balance between spine head volume and spine density. However, this inverse relationship between spine head volume and spine density was not observed in A53T-BAC- transgenic mice. Taken together, our data suggest that Parkinson's disease is accompanied by an abnormality in the mechanisms that control synapse growth and maturity. Currently, the clinical diagnosis of Parkinson's disease is based on the presence of motor symptoms. However, these symptoms only manifest after a significant proportion of dopaminergic cells have degenerated. The latent, prodromal phase is therefore of particular interest for the development of disease-modifying therapies to slow down or reverse the course of neurodegeneration. Although clinical markers to diagnose patients in the prodromal phase are gradually emerging, a structural marker that defines this phase has not yet been identified. Structural changes likely occur in the synapse before the onset of neurodegeneration. Thus, this study performed an ultrastructural analysis of synapses in a mouse model of prodromal Parkinson's disease and revealed distinct, age-dependent structural changes.