Objective: In order to elucidate very early pathologis of Parkinson’s disease (PD), we focused on synaptic pathologies in a newly developed mouse model of prodromal PD.

Background: Recent evidence implicates that the impairment of synapses and neuronal circuitry rewiring as important factors of pathogenesis in neuropsychiatric disorders. The synaptic mechanisms in PD pathogenesis remain to be elucidated, because of the absence of an animal model which replicates neuronal circuitry pathology. We generated BAC transgenic mice harboring human A53T α-synuclein gene SNCA with PD risk SNPs and its expression regulatory regions. A53T SNCA-BAC mice showed progressive neuronal loss of dopaminergic neurons in the substantia nigra and accumulation of phosphorylated α-synuclein in the cerebral cortex. A53T SNCA-BAC mice did not show obvious PD-like motor dysfunctions, however, they exhibited RBD-like behavior at the age of 10 weeks and smell disturbance at 9-month-old. In this study, we focused on presymptomatic synapse pathologies in the primary motor cortex by using A53T SNCA-BAC mice as a model of prodromal PD.

Methods: By crossing A53T SNCA-BAC mice with Thy1-EGFP mice, layer 5 pyramidal neurons in the cortex of the offspring were labeled. A cranial window was implanted 4 weeks prior to imaging. In vivo two-photon imaging was performed weekly for 4 weeks.

Results: A53T SNCA-BAC mice showed a decreasing density of dendritic spines at the age of 12 weeks, and it reached the plateau at 24-week-old. This was due to the imbalance of enhanced spine formation and elimination at the age of 12 weeks, and the imbalance was equalized in 24-week-old. Although spine formation and elimination rate were balanced when they grow up, both formation and elimination rate of the spine remained to be higher than control mice. A53T SNCA-BAC mice also exhibited lower pre-existed spine stability and newly-formed spine survivability at the age of 24 and 48 weeks. Furthermore, colocalization of presynaptic protein marker and dendritic spine was lower in A53T SNCA-BAC mice.

Conclusions: These results suggest that a synaptic loss in the primary motor cortex is occurred even in a prodromal PD model, and this synaptic loss is caused by an excess elimination of dendritic spines. After the abnormal synaptic pruning is finished, the instability of dendritic spines still remains as a neuronal circuitry pathology.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/early-synaptic-loss-and-synaptic-instability-in-a-mouse-model-of-prodromal-parkinsons-disease/