Objective: Our aim is to model cognitive dysfunction of Parkinson’s disease (PD) together with motor deficits by targeted overexpression of alpha-synuclein (a-syn) in bilateral dentate gyrus (DG) and substantia nigra (SN) of rats.

Background: Pathological aggregation of a-syn plays a key role in the neurodegenerative process of PD. Hippocampal a-syn pathology is accused to be responsible from different aspects of cognitive dysfunction seen in advancing stages of PD.

Methods: AAV-carrying a-syn (n=11) or saline (n=8) was injected bilaterally into DG and SN of female Sprague-Dawley rats (200-250g). Seven animals were used as naïve controls. All animals were tested for memory, spatial learning, anxiety, anhedonia, motor coordination and locomotion by novel object recognition (NOR), Morris water maze (MWM), elevated plus maze, sucrose preference, rotarod and locomotor activity tests respectively, 16-18 weeks following injection. Brain samples were analyzed by both Western blotting and immunohistochemistry for phosphorylated a-syn (p-a-syn), NeuN, tyrosine hydroxylase (TH) and synaptophysin. Neuronal loss in SN and hippocampus were evaluated with stereological quantification.

Results: Compared to controls, a-syn group spent shorter time with the novel object in NOR test and longer time to find the platform in MWM (p<0.05). Motor performance in rotarod and locomotor activity were lower in a-syn group, whereas increase in horizontal activity after apomorphine injection was more prominent in this group (p<0.05). P-a-syn overexpression in striatum and hippocampus was confirmed by Western blotting. Stereological count of TH-positive neurons in SN showed %43 loss (p<0.05) and synaptophysin expression levels decreased %28 in striatum, %46 in hippocampus in the a-syn group compared to naïve controls (p<0.05).

Conclusions: Previously, we did not detect significant behavioral or histological changes of bilateral DG a-syn overexpression (1). In this study, targeting both DG and SN caused behavioral deficits correlated with synaptic loss in both hippocampus and striatum while partially related to dopaminergic cell loss. We suggest that the “dual targeting” may provide a better model for cognitive impairment of PD. A-syn and GFP viral vectors were kindly obtained from Michael J Fox Foundation.

References: 1. Tel, B., Cakmakli, G.Y., Cinar, E., Mutluay, S.U., Telli, G., Saka, E., Ulusoy, A., Elibol, B., (2015). Cognitive dysfunction due to over-expression of alpha-synuclein in hippocampus by using viral vector based approach: Modeling cognitive decline in PD. Movement Disorders. 30 Suppl. 1, pages:S49-S50, abstract no: 124.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/a-promising-model-for-cognitive-dysfunction-in-parkinsons-disease-by-aav-mediated-alpha-synuclein-overexpression-in-hippocampus/