Reduction of D2 receptors on microglia leads to ZBP1-mediated PANoptosis of mPFC in Parkinson's disease depression mice.

Parkinson's disease depression (PDD) is a common non-motor symptom of Parkinson's disease (PD), characterized by complex neurobiological mechanisms that remain poorly understood. This study identifies ZBP1-mediated PANoptosis as a critical mechanism linking neuroinflammation, neuronal loss, and depressive behaviors in PDD. Using a 6-hydroxydopamine (6-OHDA)-induced PDD mouse model, we observed significant reductions in dopaminergic projections from the substantia nigra (SN) to the medial prefrontal cortex (mPFC), accompanied by neuronal loss and depressive-like behaviors. Microglial activation, driven by DRD2 downregulation, was found to impair mPFC neuronal function, as evidenced by altered local field potentials and reduced gamma, beta, and theta oscillations. Furthermore, ZBP1 expression was significantly upregulated in the mPFC of PDD mice, where it colocalized with CaMKII-positive neurons and facilitated the formation of PANoptosomes, a multimeric complex driving pyroptosis, apoptosis, and necroptosis. Knockdown of ZBP1 in the mPFC effectively suppressed PANoptosome formation, reduced neuronal injury, restored local field potentials, and alleviated depressive-like behaviors. These findings highlight ZBP1-mediated PANoptosis as a key pathological mechanism in PDD and suggest that targeting ZBP1 may represent a promising therapeutic strategy for mitigating neuronal loss and depressive symptoms in PDD.