Motor Cortical Neuronal Hyperexcitability Associated with α-Synuclein Aggregation

Area of Science:

• Neuroscience
• Neuropathology
• Movement Disorders

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 interacts with dopaminergic degeneration in PD remain unclear.
• Investigating cortical Lewy pathology is crucial for understanding PD pathogenesis.

Purpose of the Study:

• To investigate how alpha-synuclein (αSyn) aggregation impacts cortical circuit integrity and function in a mouse model of Parkinson disease (PD).
• To determine the specific effects of αSyn pathology on different neuronal subtypes within the motor cortex.
• To explore the relationship between cortical αSyn deposition and midbrain dopaminergic neuron degeneration in PD.

Main Methods:

• Injection of α-synuclein (αSyn) preformed fibrils (PFFs) into the dorsolateral striatum of mice to induce pathology.
• Analysis of αSyn aggregate distribution in specific cortical layers and neuronal subtypes (intratelencephalic neurons [ITNs] and corticospinal neurons [CSNs]).
• Electrophysiological recordings to assess neuronal intrinsic excitability, input resistance, and morphological changes (somatic size, dendritic spines).

Main Results:

• αSyn aggregates preferentially accumulated in ITNs compared to CSNs within the motor cortex.
• αSyn-laden ITNs exhibited increased intrinsic excitability and input resistance, alongside somatic shrinkage and dendritic spine loss.
• Midbrain dopaminergic neuron degeneration and associated striatal dopamine depletion did not alter CSN intrinsic excitability or thalamocortical inputs.

Conclusions:

• αSyn aggregation in motor cortex neurons leads to neuronal hyperexcitability, offering a new mechanism for cortical dysfunction in Parkinson disease (PD).
• The findings highlight a cell-type-specific vulnerability of cortical neurons to αSyn pathology.
• This study provides a mechanistic link between Lewy pathology and cortical circuit disruption in PD.