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: Zacharias Kohl, Nada Ben Abdallah, Jonathan Vogelgsang, Lucas Tischer, Janina Deusser, Davide Amato, Scott Anderson, Christian P Müller, Olaf Riess, Eliezer Masliah, Silke Nuber, Jürgen Winkler
• Journal: Neurobiology of disease (Neurobiol Dis) Vol. 85 Pg. 206-217 (Jan 2016) ISSN: 1095-953X [Electronic] United States
• PMID: 26523794 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• Doublecortin Domain Proteins
• Microtubule-Associated Proteins
• Neuropeptides
• SNCA protein, human
• alpha-Synuclein
• Serotonin
• Bromodeoxyuridine
• Dopamine

Topics

• Animals
• Blotting, Western
• Bromodeoxyuridine
• Cell Count
• Dopamine (metabolism)
• Dorsal Raphe Nucleus (pathology, physiopathology)
• Doublecortin Domain Proteins
• Exploratory Behavior (physiology)
• Feeding Behavior (physiology)
• Fluorescent Antibody Technique
• Hippocampus (pathology, physiopathology)
• Humans
• Male
• Microscopy, Electron
• Microtubule-Associated Proteins (metabolism)
• Neurogenesis (physiology)
• Neurons (pathology, physiology)
• Neuropeptides (metabolism)
• Parkinsonian Disorders (pathology, physiopathology)
• Rats, Transgenic
• Serotonin (metabolism)
• Synapses (pathology, physiology)
• alpha-Synuclein (genetics, metabolism)