Reduced Interaction of VAMP2 and Aggregated α-synuclein by Environmental Enrichment Alleviates Hyperactivity and Anxiety in a Model of Parkinson’s Disease.

Abstract

BackgroundAlthough Parkinson’s disease (PD) is one of the prevalent motor diseases caused by the accumulation of mutated α-Synuclein (α-Syn), it is characterized by non-motor symptoms such as olfactory loss, cognitive decline, depression and anxiety in the early stage of the disease. Environmental enrichment (EE) provides a complex environment comprising physical, cognitive, and social stimuli that improve synaptic plasticity and behavioral functions. The therapeutic effects of EE on behavioral recovery of motor function in a mouse model of PD pathology have been reported. However, the effects of EE on non-motor symptoms in human A53T α-Syn overexpressing transgenic (hA53T α-Syn) mice have yet to be determined. In this study, we revealed the beneficial effect of EE on changes in synaptic plasticity in the striatum and nucleus accumbens (NAc) during the initial phase of PD.MethodTo investigate therapeutic effects of EE in abnormalities during the early phase of PD, we randomly assigned eight-month-old hA53T α-Syn mice to either EE (PD-EE) or standard conditions (PD-SC) for two months. Next, we performed behavioral tests, biochemical and histological analysis at 10 months of age.ResultsEE significantly alleviated locomotor hyperactivity and anxiety in the early stage of PD. EE normalized the level of tyrosine hydroxylase (TH), phosphorylated and oligomeric forms of α-Syn (pSer129 α-Syn), and SNARE complex-forming proteins including SNAP-25, Syntaxin1 and VAMP2. Moreover, the close link between VAMP2 and pSer129 α-Syn was significantly reduced after exposure to EE.ConclusionsOur results showed that EE attenuates aversive mood state on the early stage of PD mouse model. These results were parallel with the reduced expression of pathological α-Syn and the increased expression of neurotransmitter transporter proteins in EE. Interestingly, the interaction between pSer129 α-Syn and VAMP2 also decreased in EE. The restoration of synaptic vesicle transportation status may be responsible for the neuroprotective effects of EE in hA53T α-Syn mice.