Effects of rapamycin in a rat model of adeno associated viral vector mediated nigral and hippocampal alpha-synucleinopathy

Çınar, E., Effects of Rapamycin In A Rat Model Of Adeno Associated Viral Vector Mediated Nigral and Hippocampal Alpha-synucleinopathy, Hacettepe University Graduate School of Health Sciences, Pharmacology Programme Doctor of Philosophy Thesis, Ankara, 2018. In this thesis study, we aimed to develop a Parkinson's disease (PD) model recapitulating both motor and non-motor symptoms of the disease by AAV-mediated alpha-synuclein (a-syn) overexpression in bilateral substantia nigra (SN) and dentate gyrus (DG) and to evaluate the potantial therapeutic effects of rapamycin via autophagy induction. A-syn and its viral control GFP overexpression was confirmed by immunohistochemistry and immunoblotting. A dense synaptic loss and a neuronal loss tendency were detected in a-syn group by immunblotting. First time in this model using rapamycin treatment showed a protective effect against the synaptic loss. Effect of a-syn overexpression on the motor performance was evaluated in every two weeks and a compensatory mechanism was noticed to take part in the process. Elevated plus maze test showed a decrease in anxiety whereas memory deficits, spatial learning difficulties and worsening in motor performance were detected in novel object recognition, Morris water maze, rotarod and locomotor activity tests, respectively. After rapamycin treatment improved learning and memory, increased anxiety and did not change motor performance. In immunoblotting; p62 an autophagy marker, increased with rapamycin treatment, confirming autophagic induction, on the other hand, conversion of LC3 I to LC3 II another autophagy marker decreased. This AAV-mediated a-syn overexpression model of PD, developed motor and non-motor symptoms together for the first time, can be used safely to try potential autophagy inducing treatment options like rapamycin. Key words: Parkinson's disease, Alpha-synuclein, Rapamycin, Non-motor semptoms, Synaptic loss This study (TSA-2015-5291) was supported by Hacettepe University Scientific Research Projects Coordination Unit. AAV-a-syn and AAV-GFP virus was kindly requested from Michael J. Fox.