Severely impaired hippocampal neurogenesis associates with an early serotonergic deficit in a BAC α-synuclein transgenic rat model of Parkinson's disease

NEUROBIOLOGY OF DISEASE

卷:85

Article

Kohl, Zacharias¹  Ben Abdallah, Nada¹  Vogelgsang, Jonathan¹  Tischer, Lucas¹  Deusser, Janina¹  Amato, Davide²  Anderson, Scott³  Mueller, Christian P.²  Riess, Olaf⁵  Masliah, Eliezer³  Nuber, Silke^3,4,5  Winkler, Juergen¹ 

[1] Univ Erlangen Nurnberg, Dept Mol Neurol, D-91054 Erlangen, Germany

[2] Univ Erlangen Nurnberg, Dept Psychiat & Psychotherapy, D-91054 Erlangen, Germany

[3] Univ Calif San Diego, Dept Neurosci & Pathol, La Jolla, CA 92093 USA

[4] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA

[5] Univ Tubingen, Inst Med Genet & Appl Genom, Tubingen, Germany

关键词: Parkinson's disease;    Alpha-synuclein;    Hippocampus;    5-HT;    Neurogenesis;    Dendritogenesis;    Synapse;   

DOI  :  10.1016/j.nbd.2015.10.021

来源: Elsevier

【 摘 要 】

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. (C) 2015 Elsevier Inc All rights reserved.

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