Motor Cortical Neuronal Hyperexcitability Associated with α-Synuclein Aggregation
Dysfunction of the cerebral cortex is thought to underlie motor and cognitive impairments in Parkinsons 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 -synuclein (Syn) preformed fibrils (PFFs) into the dorsolateral striatum of mice to seed Syn pathology in the cortical cortex and induce degeneration of midbrain dopaminergic neurons. Using this model system, we reported that Syn 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 Syn aggregates relative to corticospinal neurons (CSNs). Moreover, we demonstrated that the intrinsic excitability and inputs resistance of Syn 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 Syn pathology. Our results documented motor cortical neuronal hyperexcitability associated with Syn aggregation and provided a novel mechanistic understanding of cortical circuit dysfunction in PD.