Human synuclein aggregation activates ferroptosis leading to parvalbumin interneuron degeneration and motor learning impairment

The accumulation of synuclein induces neuronal loss in midbrain nuclei and leads to the disruption of motor circuits, while the pathology of synuclein in cortical regions remains elusive. To better characterize the cortical synucleinopathy, here we generate a mouse model with the overexpression of human synuclein in the primary motor cortex of mice. A combination of molecular, in vivo recording, and behavioral approaches reveal that cortical expression of human synuclein results in the over excitation of cortical pyramidal neurons , which are regulated by the decreased inhibitory inputs from parvalbumin interneurons to impair complex motor skill learning. Further mechanistic dissections reveal that human synuclein aggregation activates ferroptosis, contributing to PV interneuron degeneration and motor circuit dysfunction.