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.
Highlights
Behavioral phenotype, in a BAC transgenic rat model overexpressing the full-length human α-synuclein under a pan-neuronal promoter
We obtained high expression of GFP in neurons outside the raphe nuclei (RN), the serotonin neurons were only poorly transduced, even at high titers of the viruses. This prompted us to generate an AAV2/6 vector where the transgene is driven by a tryptophan hydroxylase (TPH) promoter sequence developed by Benzekhroufa et al.[16]
Since the impact of impaired serotonin function is known to be amplified by dysfunction in the basal forebrain cholinergic system,[17,18,19,20] we studied the effect of overexpression of α-synuclein in the presence and absence of a low dose of the cholinergic blocker scopolamine, and in animals where α-synuclein was expressed in both the RN and the cholinergic neurons of the medial septum/diagonal band of Broca (MS/DB) area
Summary
Behavioral phenotype, in a BAC transgenic rat model overexpressing the full-length human α-synuclein under a pan-neuronal promoter. Hall et al.[15] used a α-synuclein expressing AAV2/5 vector to induce long-term degenerative changes in cholinergic neurons of the medial septum/diagonal band of Broca (MS/DB) area in rats. This approach has not been explored in the serotonin neurons of the RN. We obtained high expression of GFP in neurons outside the RN, the serotonin neurons were only poorly transduced, even at high titers of the viruses This prompted us to generate an AAV2/6 vector where the transgene is driven by a tryptophan hydroxylase (TPH) promoter sequence developed by Benzekhroufa et al.[16]. Since the impact of impaired serotonin function is known to be amplified by dysfunction in the basal forebrain cholinergic system,[17,18,19,20] we studied the effect of overexpression of α-synuclein in the presence and absence of a low dose of the cholinergic blocker scopolamine, and in animals where α-synuclein was expressed in both the RN and the cholinergic neurons of the MS/DB area
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