Intranasal α-Synuclein induces progressive behavioral impairments in mice

Abstract

α-Synuclein (α-Syn) is implicated in the progression of Parkinson's disease, yet the disease's etiology remains unclear. This study aims to explore how α-Syn affects olfactory, motor, mood and cognitive functions if it initiates from the olfactory bulb. Mice were administered intranasal human AAV-α-Syn and subsequently evaluated for olfactory, motor, mood, and cognitive functions. Immunofluorescence was performed to assess dopaminergic neuronal damage. Results shown that olfactory dysfunction was evident as AAV-α-Syn-treated mice took longer to find buried pellets compared to controls at 3, 9, and 12 months post-instillation. Motor activity remained normal at 6 months but significantly declined at 9 months. Reduced tyrosine hydroxylase expression but increased amount of human α-Syn were observed in the substantia nigra at end of behavioral measurements. AAV-α-Syn mice showed reduced sucrose intake and decreased time in the center zone of the open field at 9 months. Cognitive deficits were observed in recognition function and social memory at 6 and 9 months, with impaired working memory at 12 months. Thus, intranasal AAV-α-Syn instillation in mice leads to progressive olfactory, motor, anxiety, depression-like, and cognitive dysfunctions, reflecting α-Syn pathology propagation.