Seeding and transgenic overexpression of alpha‐synuclein triggers dendritic spine pathology in the neocortex

Abstract Although misfolded and aggregated α‐synuclein (α‐syn) is recognized in the disease progression of synucleinopathies, its role in the impairment of cortical circuitries and synaptic plasticity remains incompletely understood. We investigated how α‐synuclein accumulation affects synaptic plasticity in the mouse somatosensory cortex using two distinct approaches. Long‐term in vivo imaging of apical dendrites was performed in mice overexpressing wild‐type human α‐synuclein. Additionally, intracranial injection of preformed α‐synuclein fibrils was performed to induce cortical α‐syn pathology. We find that α‐synuclein overexpressing mice show decreased spine density and abnormalities in spine dynamics in an age‐dependent manner. We also provide evidence for the detrimental effects of seeded α‐synuclein aggregates on dendritic architecture. We observed spine loss as well as dystrophic deformation of dendritic shafts in layer V pyramidal neurons. Our results provide a link to the pathophysiology underlying dementia associated with synucleinopathies and may enable the evaluation of potential drug candidates on dendritic spine pathology in vivo.