Neurochemical and Behavioral Effects of Alpha-Synuclein Oligomers in Three-Month-Old Mice

—Parkinson’s disease is a widespread, progressive, age-related neurodegenerative disease. The neurochemical basis of motor and non-motor disorder in Parkinson’s disease is the dysfunction of many neurotransmitter systems of the brain and, first of all, the functional deficit and imbalance of monoaminergic systems, which result from the degradation and death of certain populations of nerve cells caused by misfolding of the α-synuclein protein and the action of its amyloidogenic neurotoxic conformations. Analysis of age-related changes in monoaminergic systems and the development of motor and non-motor disorders at the preclinical and clinical stages of the disease are of particular interest. We studied the effect of α-synuclein oligomers administered intranasally for 14 days on locomotor activity, emotional state, short- and long-term memory, and the content and metabolism of dopamine, serotonin, and norepinephrine in the hippocampus, frontal cortex, and cerebellum of male C57Bl/6 mice at the age of 3 months. In behavioral experiments, the following tests were used: “open field,” “novel object recognition,” “passive avoidance,” and “elevated plus maze.” The content of monoamines and their metabolites in the brain tissue of animals was determined by high performance liquid chromatography with electromagnetic detection. It was found that mice treated with α-synuclein oligomers showed manifestations of affective-like behavior with signs of apathy. The animals showed no disorders in motor activity, short-term and long-term memory, and no changes in anxiety level. Oligomers of α-synuclein caused a significant decrease in the content of dopamine and its metabolites DOPAC and HVA in the frontal cortex, as well as a decrease in the concentration of the dopamine metabolite, 3-MT, and opposite directed changes in serotonin and dopamine metabolism in the hippocampus. However, a significant increase in the content of 3-MT in the cerebellum was recorded. We performed comparative analysis of the data obtained in this work and the results of our previous study of the neurochemical and behavioral effects of α-synuclein oligomers in 6-month-old mice. The results indicate that oligomers of α‑synuclein, when administered chronically intranasally, induce non-motor disorders and neurochemical changes in mice of 3 months of age, which are also observed at the preclinical stage of PD.