Motor Cortical Neuronal Hyperexcitability Associated with α-Synuclein Aggregation.

Area of Science:

• Neuroscience
• Neuropathology
• Parkinsons Disease Research

Background:

• Cerebral cortex dysfunction contributes to motor and cognitive deficits in Parkinson disease (PD).
• The precise mechanisms by which Lewy pathology disrupts cortical circuits and function, especially in interaction with dopaminergic degeneration, remain unclear.
• Understanding cortical involvement is crucial for developing targeted PD therapies.

Purpose of the Study:

• To investigate how alpha-synuclein (αSyn) pathology affects cortical circuit integrity and neuronal function in a mouse model of Parkinson disease.
• To determine the specific patterns of αSyn aggregate accumulation in the motor cortex and their impact on different neuronal subtypes.
• To elucidate the relationship between cortical αSyn pathology and midbrain dopaminergic neuron degeneration in disrupting cortical function.

Main Methods:

• Injection of alpha-synuclein (αSyn) preformed fibrils (PFFs) into the dorsolateral striatum of mice to induce pathology.
• Analysis of αSyn aggregate deposition in specific layers and cell subtypes within the motor cortex.
• Electrophysiological recordings and morphological analyses of intratelencephalic neurons (ITNs) and corticospinal neurons (CSNs).

Main Results:

• αSyn aggregates accumulated in a layer- and cell-subtype-specific manner in the motor cortex, with earlier and more extensive deposition in intratelencephalic neurons (ITNs) compared to corticospinal neurons (CSNs).
• αSyn-bearing ITNs in the secondary motor cortex (M2) exhibited increased intrinsic excitability and input resistance, alongside cell body shrinkage and dendritic spine loss.
• Neither CSN intrinsic excitability nor their thalamocortical input was affected by the associated striatal dopamine depletion.

Conclusions:

• Cortical αSyn aggregation leads to neuronal hyperexcitability, particularly in ITNs, offering a novel mechanistic insight into cortical circuit dysfunction in Parkinson disease.
• The findings highlight a distinct pathway of cortical pathology independent of significant dopaminergic depletion effects on specific neuronal populations.
• This study provides a foundation for understanding how Lewy pathology directly impacts cortical function in PD pathogenesis.