title: 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-termin vivoimaging 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 pathologyin vivo.
authors.affiliation: Center for Neuropathology and Prion Research, Ludwig-Maximilians University, Munich, Germany.|German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.|Munich Cluster of Systems Neurology (SyNergy), Munich, Germany.
authors.forename: Sonja
authors.identifier: 0000-0002-8124-3295
authors.initials: S
authors.lastname: Blumenstock
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
authors.forename: Eva F
authors.initials: EF
authors.lastname: Rodrigues
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
authors.forename: Finn
authors.identifier: 0000-0002-3062-9825
authors.initials: F
authors.lastname: Peters
authors.affiliation: Departamento de Psicobiología, Universidad Nacional de Educación a Distancia (UNED), Madrid, Spain.
authors.forename: Lidia
authors.identifier: 0000-0002-4865-8974
authors.initials: L
authors.lastname: Blazquez-Llorca
authors.affiliation: Center for Neuropathology and Prion Research, Ludwig-Maximilians University, Munich, Germany.|Department of Neurology, Ludwig-Maximilians University, Munich, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Schmidt
authors.affiliation: Center for Neuropathology and Prion Research, Ludwig-Maximilians University, Munich, Germany.
authors.forename: Armin
authors.identifier: 0000-0002-8238-4102
authors.initials: A
authors.lastname: Giese
authors.affiliation: Center for Neuropathology and Prion Research, Ludwig-Maximilians University, Munich, Germany jochen.herms@med.uni-muenchen.de.|German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.|Munich Cluster of Systems Neurology (SyNergy), Munich, Germany.
authors.forename: Jochen
authors.identifier: 0000-0002-6201-1042
authors.initials: J
authors.lastname: Herms
mesh_terms: D000375:Aging; D000818:Animals; D049229:Dendritic Spines / Q000235:genetics / Q000473:pathology*; D005260:Female; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019579:Neocortex / Q000378:metabolism / Q000473:pathology*; D066263:Protein Aggregation, Pathological / Q000235:genetics / Q000473:pathology*; D017966:Pyramidal Cells / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation; D051844:alpha-Synuclein / Q000235:genetics*
chemical_list: C497604:SNCA protein, human; D051844:alpha-Synuclein
keywords: alpha‐synuclein; dendritic spines; in vivo imaging; seeding; synucleinopathies