Neuronal HIPK2-HDAC3 axis regulates mitochondrial fragmentation to participate in stroke injury and post-stroke anxiety like behavior

Post-stroke anxiety (PSA) seriously affects the prognosis of patients, which is an urgent clinical problem to be addressed. However, the pathological mechanism of PSA is largely unclear. Here, we found that neuronal HIPK2 expression was upregulated in the ischemic lesion after stroke. The upregulation of HIPK2 promotes Drp1 oligomerization through the HDAC3-dependent pathway, leading to excessive mitochondrial damage. This subsequently triggers the release of cellular cytokines such as IL-18 from neurons under ischemic stress. Microglia are capable of responding to IL-18, which promotes their activation and enhances their phagocytosis, ultimately resulting in the loss of synapses and neurons, thereby exacerbating the pathological progression of PSA. HIPK2 knockdown or inhibition suppresses excessive pruning of neuronal synapses by activated microglia in the contralateral vCA1 region to compromise inactivated anxiolytic pBLA-vCA1