Intranasal α-Synuclein induces progressive behavioral impairments in mice

Area of Science:

• Neuroscience
• Pathology
• Animal Models

Background:

• Alpha-synuclein (α-Syn) aggregation is a hallmark of Parkinson's disease (PD).
• The precise initiation and propagation pathways of α-Syn pathology in PD remain incompletely understood.
• Investigating the olfactory bulb as a potential starting point for α-Syn pathology is crucial for understanding PD etiology.

Purpose of the Study:

• To investigate the functional consequences of initiating α-Syn pathology in the olfactory bulb.
• To assess the impact of intranasal α-Syn administration on olfactory, motor, mood, and cognitive functions in a mouse model.
• To evaluate the propagation of α-Syn pathology and its effect on dopaminergic neurons.

Main Methods:

• Administration of adeno-associated virus carrying human α-Syn (AAV-α-Syn) via intranasal instillation in mice.
• Longitudinal behavioral assessments including olfactory, motor, anxiety, depression-like, and cognitive tests.
• Immunofluorescence analysis to quantify α-Syn levels and assess dopaminergic neuronal integrity (tyrosine hydroxylase expression) in the substantia nigra.

Main Results:

• Progressive olfactory dysfunction was observed starting at 3 months post-instillation.
• Motor activity declined significantly by 9 months, while mood and anxiety-like behaviors were altered at 9 months.
• Cognitive deficits, including impaired recognition, social memory, and working memory, emerged at 6-12 months.
• Increased human α-Syn and reduced tyrosine hydroxylase expression were detected in the substantia nigra.

Conclusions:

• Intranasal AAV-α-Syn instillation in mice successfully models the initiation and propagation of α-Syn pathology.
• This model demonstrates that olfactory bulb α-Syn pathology leads to widespread functional deficits mirroring Parkinson's disease.
• Findings support the olfactory bulb as a potential primary site for α-Syn pathology in Parkinson's disease progression.