Cell-Type-Selective Cortical Pathology and Functional Deficits in Synucleinopathy.

Area of Science:

• Neuroscience
• Pathology
• Molecular Biology

Background:

• Synucleinopathies are characterized by alpha-synuclein (α-syn) aggregates in the cerebral cortex, correlating with motor symptoms and altered neuronal activity.
• The precise mechanisms linking α-syn pathology to cortical network dysfunction and impaired motor control remain unclear.

Purpose of the Study:

• To investigate the pathophysiological characteristics of early-stage synucleinopathy in a mouse model with minimal nigrostriatal degeneration.
• To elucidate the cell-type-specific alterations in cortical neurons and their contribution to motor deficits.

Main Methods:

• Utilized a multi-disciplinary approach including in vivo two-photon imaging and ex vivo whole-cell recordings.
• Examined transgenic mice expressing mutant human α-syn to assess cortical neuronal activity and α-syn inclusion patterns.

Main Results:

• Identified distinct alteration patterns in excitatory and parvalbumin (PV)-expressing inhibitory cortical neurons during fine motor learning.
• Observed selectively altered intrinsic properties in excitatory neurons, with preferential α-syn accumulation in these cells compared to PV neurons.

Conclusions:

• Demonstrated cell-type-selective vulnerability of excitatory neurons in the motor cortex during early synucleinopathy.
• Concluded that disrupted excitatory/inhibitory balance and dysregulated cortical plasticity in these vulnerable neurons drive early motor symptoms.