Objective: To evaluate the impact of α-synuclein accumulation on the hippocampal serotonergic system and hippocampal plasticity in two different α-synuclein expressing rodent models.

Background: Parkinson’s disease (PD) involves several monoaminergic neurotransmitter systems resulting in a broad range of motor and non-motor symptoms (NMS). The accumulation of α-synuclein, the pathological hallmark of PD, is present in serotonergic raphe nuclei early in the disease course. The dysfunction of the serotonergic system projecting to the hippocampus might contribute to early NMS such as anxiety and depression.

Methods: We used two different transgenic rodent models, BAC α-synuclein transgenic rats and mice overexpressing mutant A53T α-synuclein to determine the hippocampal serotonergic system and its impact on the circuitry in the hippocampal dentate gyrus (DG). We analyzed cellular and neuritic plasticity in the DG by immunohistochemistry, together with a morphological analysis of serotonin (5-HT) fiber density. Alterations of the 5-HT system were further determined by HPLC and western blot analysis. Finally, we investigated the response of DG neurogenesis to chronic antidepressant treatment with fluoxetine in A53T α-synuclein mice.

Results: In α-synuclein rats, we observed a profound loss of dendrites and axons in the DG resulting in reduced survival of new-born neurons at the age of 4 months, prior to the onset of motor symptoms. The diminished neurogenesis concurred with reduced hippocampal levels of 5-HT 1B receptor, decreased 5-HT levels and a loss of serotonergic axons innervating the DG. Complementary, the A53T α-synuclein mice show α-synuclein aggregation in 5-HT neurons of the raphe nuclei together with a reduced serotonergic innervation of the dorsal DG at the age of 12 months. Interestingly, we observed a significantly compromised increase of DG neuroblasts after chronic treatment with fluoxetine at the site of reduced serotonergic innervation, the infrapyramidal blade of the dorsal DG.

Conclusions: These findings imply that accumulating α-synuclein reduces hippocampal neurogenesis and serotonergic axonal projections prior to the onset of motor deficits. Moreover, α-synuclein accumulation results in a spatially distinct pattern of reduced serotonergic input to the hippocampus likely determining the limited response to antidepressant treatment.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/impaired-hippocampal-neurogenesis-associates-with-serotonergic-axonal-degeneration-in-transgenic-rat-and-mouse-models-of-parkinsons-disease/