?-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 ?-synuclein overexpression in brainstem serotonin neurons using a novel vector construct where the expression of human wildtype ?-synuclein is driven by the tryptophan hydroxylase promoter, allowing expression of ?-synuclein at elevated levels, and with high selectivity, in serotonergic neurons. ?-Synuclein induced degenerative changes in axons and dendrites, displaying a distorted appearance, suggesting accumulation and aggregation of ?-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 ?-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 ?-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 ?-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.

SUBMITTER: Wan OW 

PROVIDER: S-EPMC4876322 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature