Enhanced Microglial Engulfment of Dopaminergic Synapses Induces Parkinson's Disease‐Related Executive Dysfunction in an Acute LPC Infusion Targeting the mPFC

The dysfunction of the dopaminergic projection from the ventral tegmental area (VTA) to the medial prefrontal cortex (mPFC) is believed to play a key role in the pathophysiology of Parkinson's disease (PD) accompanied by executive dysfunction (EDF). In this study, we identified an abnormal increase in lysophosphatidylcholine (LPC) levels in PD patients, which closely correlates with the severity of cognitive impairment. LPC disrupts the miR-2885/TDP-43 signaling pathway in microglia, driving dopaminergic presynaptic engulfment. In LPC-exposed mice, microglial activation via miR-2885/TDP-43/p65 signaling led to inflammatory cytokine and complement release, marking dopaminergic synapses for phagocytosis with a "PS/C1q" signal. Following the inhibition of LPC-induced microglial activation through chemogenetic methods, we observed a significant reduction in the phagocytosis of dopaminergic synapses, resulting in improved executive function. The miR-2885 disrupted LPC-induced dopaminergic phagocytosis and alleviated EDF. Furthermore, the accumulation of excessive TDP-43 due to the loss of miR-2885 promoted the engulfment of dopaminergic synapses by facilitating the entry of p65 into the nucleus. Inhibiting TDP-43 levels effectively mitigated LPC-induced EDF. Additionally, supplementing dopamine receptor agonists enhanced the excitability of regional glutamatergic neurons, leading to improved executive function. In summary, LPC exposure in the mPFC impairs microglial regulation, leading to dopaminergic synaptic loss and underactivity of glutamatergic neurons. These changes drive the development of executive dysfunction in PD.