title: Serotonergic dysfunction in the A53T alpha-synuclein mouse model of Parkinson's disease.
abstract: Parkinson's disease, neuropathologically defined by the aggregation of α-synuclein, is characterized by neuropsychiatric symptoms such as depression and anxiety preceding the onset of motor symptoms. A loss of serotonergic neurons or their projections into the hippocampus and alterations in serotonin release may be linked to these symptoms. Here, we investigate the effect of human A53T α-synuclein on serotonergic neurons using 12-months-old transgenic mice. We detected human α-synuclein in the perikarya of brainstem median and dorsal raphe neurons as well as in serotonergic fibers in the hippocampus. Despite intracellular α-synuclein accumulation there was no loss of serotonergic neurons in dorsal and median raphe nuclei of A53T α-synuclein mice. However, serotonin levels were significantly reduced in the brainstem. In addition, serotonergic fiber density in the dorsal dentate gyrus was significantly less dense in transgenic mice. Interestingly, we detected a significantly compromised increase in doublecortin+ neuroblasts after chronic treatment with fluoxetine at the site of reduced serotonergic innervation, the infrapyramidal blade of the dorsal dentate gyrus in A53T α-synuclein mice. This suggests that α-synuclein affects serotonergic projections in a spatially distinct pattern within the hippocampus thereby influencing the response to antidepressant treatment.
authors.affiliation: Department of Molecular Neurology, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Janina
authors.initials: J
authors.lastname: Deusser
authors.affiliation: Department of Molecular Neurology, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Schmidt
authors.affiliation: Department of Molecular Neurology, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Ettle
authors.affiliation: Department of Molecular Neurology, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Sonja
authors.initials: S
authors.lastname: Plötz
authors.affiliation: Section of Addiction Medicine, Department of Psychiatry and Psychotherapy, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Huber
authors.affiliation: Section of Addiction Medicine, Department of Psychiatry and Psychotherapy, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Christian P
authors.initials: CP
authors.lastname: Müller
authors.affiliation: Department of Neurosciences and Pathology, University of California San Diego, La Jolla, California, USA.
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
authors.affiliation: Department of Molecular Neurology, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Winkler
authors.affiliation: Department of Molecular Neurology, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Zacharias
authors.initials: Z
authors.lastname: Kohl
mesh_terms: D000818:Animals; D001933:Brain Stem / Q000378:metabolism; D004195:Disease Models, Animal; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism*; D059326:Serotonergic Neurons / Q000378:metabolism* / Q000473:pathology; D012701:Serotonin / Q000378:metabolism*; D051844:alpha-Synuclein / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D051844:alpha-Synuclein; D012701:Serotonin
keywords: A53T alpha-synuclein; Parkinson's disease; SERT; adult hippocampal neurogenesis; raphe nuclei; serotonin