Impaired Fast Network Oscillations and Mitochondrial Dysfunction in a Mouse Model of Alpha-synucleinopathy (A30P)

Area of Science:

• Neuroscience
• Mitochondrial Biology
• Neurodegenerative Diseases

Background:

• Intracellular accumulation of alpha-synuclein (α-syn) is a hallmark of Lewy body dementias (LBDs), such as Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB).
• LBDs are characterized by significant cognitive impairments and alterations in brain network activity.

Purpose of the Study:

• To investigate how abnormal α-syn expression affects cortical network oscillations, specifically gamma frequency activity in the hippocampus, which is crucial for cognitive function.
• To explore the underlying mechanisms, including mitochondrial dysfunction, contributing to these network changes.

Main Methods:

• Utilized a mouse model overexpressing human mutant α-syn (A30P).
• Recorded hippocampal network oscillations in brain slices from young (2-6 months) and aged (9-16 months) A30P and control mice.
• Assessed mitochondrial function using mitochondrial blockers (potassium cyanide, rotenone) and measured cytochrome c oxidase (COX) activity and expression.

Main Results:

• Aged A30P mice exhibited an age-dependent reduction in gamma (20-80 Hz) oscillation power, not observed in young A30P or control mice.
• Mitochondrial blockers caused a greater reduction in network oscillations in aged A30P mice compared to controls.
• Histochemical and immunohistochemical analyses revealed age-dependent decreases in COX activity and COX IV expression in aged A30P mice, indicating mitochondrial dysfunction.

Conclusions:

• Overexpression of α-syn leads to age-dependent mitochondrial dysfunction.
• Impaired mitochondrial function is associated with reduced gamma frequency network activity in the hippocampus.
• These findings offer mechanistic insights into how α-syn pathology may drive cognitive decline in LBDs.