title: α-Synuclein induced toxicity in brain stem serotonin neurons mediated by an AAV vector driven by the tryptophan hydroxylase promoter.
abstract: We studied the impact of α-synuclein overexpression in brainstem serotonin neurons using a novel vector construct where the expression of human wildtype α-synuclein is driven by the tryptophan hydroxylase promoter, allowing expression of α-synuclein at elevated levels, and with high selectivity, in serotonergic neurons. α-Synuclein induced degenerative changes in axons and dendrites, displaying a distorted appearance, suggesting accumulation and aggregation of α-synuclein as a result of impaired axonal transport, accompanied by a 40% loss of terminals, as assessed in the hippocampus. Tissue levels of serotonin and its major metabolite 5-HIAA remained largely unaltered, and the performance of the α-synuclein overexpressing rats in tests of spatial learning (water maze), anxiety related behavior (elevated plus maze) and depressive-like behavior (forced swim test) was not different from control, suggesting that the impact of the developing axonal pathology on serotonin neurotransmission was relatively mild. Overexpression of α-synuclein in the raphe nuclei, combined with overexpression in basal forebrain cholinergic neurons, resulted in more pronounced axonal pathology and significant impairment in the elevated plus maze. We conclude that α-synuclein pathology in serotonergic or cholinergic neurons alone is not sufficient to impair non-motor behaviors, but that it is their simultaneous involvement that determines severity of such symptoms.
authors.affiliation: Wallenberg Neuroscience Center, Department of Experimental Medical Sciences, Lund University, BMC A11, Lund 22184, Sweden.
authors.forename: Oi Wan
authors.initials: OW
authors.lastname: Wan
authors.affiliation: Wallenberg Neuroscience Center, Department of Experimental Medical Sciences, Lund University, BMC A11, Lund 22184, Sweden.
authors.forename: Eunju
authors.initials: E
authors.lastname: Shin
authors.affiliation: Wallenberg Neuroscience Center, Department of Experimental Medical Sciences, Lund University, BMC A11, Lund 22184, Sweden.
authors.forename: Bengt
authors.initials: B
authors.lastname: Mattsson
authors.affiliation: Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institute, Stockholm 17176, Sweden.
authors.forename: Dorian
authors.initials: D
authors.lastname: Caudal
authors.affiliation: Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institute, Stockholm 17176, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Svenningsson
authors.affiliation: Wallenberg Neuroscience Center, Department of Experimental Medical Sciences, Lund University, BMC A11, Lund 22184, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Björklund
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D001933:Brain Stem / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D059329:Cholinergic Neurons / Q000378:metabolism / Q000473:pathology; D000229:Dependovirus / Q000235:genetics; D005260:Female; D005822:Genetic Vectors; D006801:Humans; D018782:Maze Learning; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic; D011903:Raphe Nuclei / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D059326:Serotonergic Neurons / Q000378:metabolism* / Q000473:pathology*; D014365:Tryptophan Hydroxylase / Q000235:genetics; D015854:Up-Regulation; D051844:alpha-Synuclein / Q000235:genetics* / Q000378:metabolism*
chemical_list: D011994:Recombinant Proteins; C497604:SNCA protein, human; D051844:alpha-Synuclein; D014365:Tryptophan Hydroxylase