Hippocampal Neurogenesis, Dopaminergic Neurons of the Substantia Nigra, and Behavior after Intranasal Administration of Native α-Synuclein Protein to Ageing Mice

We studied the effects of intranasal administration of native alpha-synuclein, whose hyperproduction and misfolding are the key link in the pathogenesis of Parkinson's disease and other age-related neurodegenerative diseases, on hippocampal neurogenesis, the number of dopaminergic neurons in the substantia nigra, locomotor activity, learning, memory, and anxiety level in ageing animals. The experiments were performed with 12-month-old C57BL/6 male mice which were treated for 14 days with a solution of recombinant native alpha-synuclein or physiological saline once every 24 hours. To evaluate behavioral indices, the following tests were used: open field, novel object recognition, conditioned passive avoidance response, and elevated plus maze. Proliferating cells, immature neurons, and dopaminergic nerve cells were immunohistochemically detected using antibodies against bromodeoxyuridine, doublecortin, and tyrosine hydroxylase. It was demonstrated that alpha-synuclein causes a considerable increase in the number of proliferating cells and a decrease in the number of immature neurons in the dentate gyrus the hippocampus, as well as a decrease in the density of dopaminergic neurons in the substantia nigrapars compacta. Mice that received native alpha-synuclein demonstrated lower locomotion speed, impairments in long-term associative memory, and changes in anxiety-like behavior. We compared the obtained data with the previous results on the effects of alpha-synuclein oligomers and fibrils under similar experimental protocols. The data are viewed as experimental evidence of the impairment of postnatal neurogenesis during the development of synucleinopathies and support the notion that different alpha-synuclein conformations cause the development of different neurodegenerative diseases.