# Motor Cortical Neuronal Hyperexcitability Associated with α-Synuclein Aggregation

## TL;DR

This study shows that α-synuclein aggregation in the motor cortex causes hyperexcitability in specific neurons, contributing to dysfunction in Parkinson's disease.

## Contribution

The study reveals a novel mechanism of cortical dysfunction in Parkinson's disease linked to α-synuclein aggregation and neuronal hyperexcitability.

## Key findings

- α-synuclein aggregates accumulate in a layer- and cell-subtype-specific pattern in the motor cortex.
- Intratelencephalic neurons show increased intrinsic excitability and structural changes due to α-synuclein aggregation.
- Corticospinal neurons are less affected by α-synuclein pathology and dopamine depletion.

## Abstract

Dysfunction of the cerebral cortex is thought to underlie motor and cognitive impairments in Parkinson disease (PD). While cortical function is known to be suppressed by abnormal basal ganglia output following dopaminergic degeneration, it remains to be determined how the deposition of Lewy pathology disrupts cortical circuit integrity and function. Moreover, it is also unknown whether cortical Lewy pathology and midbrain dopaminergic degeneration interact to disrupt cortical function in late-stage. To begin to address these questions, we injected α-synuclein (αSyn) preformed fibrils (PFFs) into the dorsolateral striatum of mice to seed αSyn pathology in the cortical cortex and induce degeneration of midbrain dopaminergic neurons. Using this model system, we reported that αSyn aggregates accumulate in the motor cortex in a layer- and cell-subtype-specific pattern. Particularly, intratelencephalic neurons (ITNs) showed earlier accumulation and greater extent of αSyn aggregates relative to corticospinal neurons (CSNs). Moreover, we demonstrated that the intrinsic excitability and inputs resistance of αSyn aggregates-bearing ITNs in the secondary motor cortex (M2) are increased, along with a noticeable shrinkage of cell bodies and loss of dendritic spines. Last, neither the intrinsic excitability of CSNs nor their thalamocortical input was altered by a partial striatal dopamine depletion associated with αSyn pathology. Our results documented motor cortical neuronal hyperexcitability associated with αSyn aggregation and provided a novel mechanistic understanding of cortical circuit dysfunction in PD.