title: Severely impaired hippocampal neurogenesis associates with an early serotonergic deficit in a BAC α-synuclein transgenic rat model of Parkinson's disease.
abstract: Parkinson's disease (PD) is a multisystem disorder, involving several monoaminergic neurotransmitter systems resulting in a broad range of motor and non-motor symptoms. Pathological hallmarks of PD are the loss of dopaminergic neurons and the accumulation of alpha-synuclein, however also being present in the serotonergic raphe nuclei early in the disease course. The dysfunction of the serotonergic system projecting to the hippocampus may contribute to early non-motor symptoms such as anxiety and depression. The adult hippocampal dentate gyrus (DG), a unique niche of the forebrain continuously generating new neurons, may particularly present enhanced susceptibility towards accumulating alpha-synuclein levels. The underlying molecular mechanisms in the context of neuronal maturation and survival of new-born neurons are yet not well understood. To characterize the effects of overexpression of human full-length alpha-synuclein on hippocampal cellular and synaptic plasticity, we used a recently generated BAC alpha-synuclein transgenic rat model showing important features of PD such as widespread and progressive alpha-synuclein aggregation pathology, dopamine loss and age-dependent motor decline. At the age of four months, thus prior to the occurrence of the motor phenotype, we observed a profoundly impaired dendritogenesis of neuroblasts in the hippocampal DG resulting in severely reduced survival of adult new-born neurons. Diminished neurogenesis concurred with a serotonergic deficit in the hippocampus as defined by reduced levels of serotonin (5-HT) 1B receptor, decreased 5-HT neurotransmitter levels, and a loss of serotonergic nerve terminals innervating the DG/CA3 subfield, while the number of serotonergic neurons in the raphe nuclei remained unchanged. Moreover, alpha-synuclein overexpression reduced proteins involved in vesicle release, in particular synapsin-1 and Rab3 interacting molecule (RIM3), in conjunction with an altered ultrastructural architecture of hippocampal synapses. Importantly, BAC alpha-synuclein rats showed an early anxiety-like phenotype consisting of reduced exploratory behavior and feeding. Taken together, these findings imply that accumulating alpha-synuclein severely affects hippocampal neurogenesis paralleled by impaired 5-HT neurotransmission prior to the onset of aggregation pathology and overt motor deficits in this transgenic rat model of PD.
authors.affiliation: Department of Molecular Neurology, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Zacharias
authors.initials: Z
authors.lastname: Kohl
authors.affiliation: Department of Molecular Neurology, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Nada
authors.initials: N
authors.lastname: Ben Abdallah
authors.affiliation: Department of Molecular Neurology, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Vogelgsang
authors.affiliation: Department of Molecular Neurology, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Lucas
authors.initials: L
authors.lastname: Tischer
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 Psychiatry and Psychotherapy, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Davide
authors.initials: D
authors.lastname: Amato
authors.affiliation: Department of Neurosciences and Pathology, University of California, San Diego, La Jolla, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Anderson
authors.affiliation: Department of Psychiatry and Psychotherapy, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Christian P
authors.initials: CP
authors.lastname: Müller
authors.affiliation: Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
authors.forename: Olaf
authors.initials: O
authors.lastname: Riess
authors.affiliation: Department of Neurosciences and Pathology, University of California, San Diego, La Jolla, USA.
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
authors.affiliation: Department of Neurosciences and Pathology, University of California, San Diego, La Jolla, USA; Department of Psychiatry, University of California, San Diego, La Jolla, USA; Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany. Electronic address: snuber@partners.org.
authors.forename: Silke
authors.initials: S
authors.lastname: Nuber
authors.affiliation: Department of Molecular Neurology, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany. Electronic address: juergen.winkler@uk-erlangen.de.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Winkler
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001973:Bromodeoxyuridine; D002452:Cell Count; D004298:Dopamine / Q000378:metabolism; D065847:Dorsal Raphe Nucleus / Q000473:pathology / Q000503:physiopathology; D000089622:Doublecortin Domain Proteins; D005106:Exploratory Behavior / Q000502:physiology; D005247:Feeding Behavior / Q000502:physiology; D005455:Fluorescent Antibody Technique; D006624:Hippocampus / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D008297:Male; D008854:Microscopy, Electron; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D055495:Neurogenesis / Q000502:physiology*; D009474:Neurons / Q000473:pathology / Q000502:physiology; D009479:Neuropeptides / Q000378:metabolism; D020734:Parkinsonian Disorders / Q000473:pathology / Q000503:physiopathology*; D055647:Rats, Transgenic; D012701:Serotonin / Q000378:metabolism; D013569:Synapses / Q000473:pathology / Q000502:physiology; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: D000089622:Doublecortin Domain Proteins; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides; C497604:SNCA protein, human; D051844:alpha-Synuclein; D012701:Serotonin; D001973:Bromodeoxyuridine; D004298:Dopamine
keywords: 5-HT; Alpha-synuclein; Dendritogenesis; Hippocampus; Neurogenesis; Parkinson's disease; Synapse