Motor cortical neuronal hyperexcitability associated with α-synuclein aggregation.

Area of Science:

• Neuroscience
• Cell Biology
• Neuropathology

Background:

• Parkinson's disease (PD) involves Lewy pathology in the cerebral cortex, but its impact on cortical circuits is unclear.
• Alpha-synuclein (αSyn) aggregation is a hallmark of PD, yet its precise role in cortical dysfunction needs elucidation.

Purpose of the Study:

• To investigate how αSyn pathology disrupts cortical circuit integrity and function in a mouse model of PD.
• To identify specific cellular and molecular mechanisms underlying cortical dysfunction in Parkinson's disease.

Main Methods:

• Injected αSyn preformed fibrils (PFFs) into the mouse dorsolateral striatum to induce pathology.
• Analyzed αSyn aggregate distribution, neuronal excitability, morphology, and channel function in the motor cortex.
• Assessed thalamocortical transmission following partial dopamine depletion.

Main Results:

• αSyn aggregates selectively accumulated in specific cortical layers and intratelencephalic neurons (ITNs).
• αSyn-bearing ITNs exhibited hyperexcitability, altered input resistance and capacitance, linked to impaired HCN channel function.
• ITNs with αSyn aggregates showed morphological changes, including cell body shrinkage and dendritic spine loss.
• Partial dopamine depletion did not affect thalamocortical transmission to cortical pyramidal neurons.

Conclusions:

• αSyn pathology directly impairs cortical circuit function by altering the properties of specific neuronal subtypes.
• Impaired HCN channel function and morphological changes in ITNs contribute to cortical dysfunction in Parkinson's disease.
• This study provides a mechanistic understanding of cortical circuit disruption in Parkinson's disease pathogenesis.