Cerebral ischemia-reperfusion causes a down regulation of HCN1 expression via enhancing the nuclear NRSF-HDAC4 gathering that contributes to neuron damage.

Cerebral ischemia-reperfusion (I/R) can trigger neuronal death through several biologically plausible pathways, but its underlying neurobiological mechanisms remain unclear. In this study, we tested whether hyperpolarization-activated cyclic nucleotide-gated channel 1 (HCN1) is altered in I/R that contributes to neuron damage and further clarified the mechanisms underlying this process. Cerebral I/R injury was induced by middle cerebral artery occlusion (MCAO) surgery followed by reperfusion in rats or simulated by oxygen-glucose deprivation/reoxygenation (OGD/R) in cultured cell. After reperfusion, the mRNA and protein levels of HCN1 were tested by RT-PCR and Western blot (WB). The histone deacetylases 4 (HDAC4) shuttling and the nuclear neuron-restrictive silencer factor (NRSF) expression were evaluated by WB and immunohistochemistry. Our data showed that I/R caused a strong decrease of HCN1 subunit in both hippocampus and cortex of rat. Additionally, the nuclear expression of HDAC4 and NRSF were significantly increased. In vitro OGD/R model, the gathering of HDAC4 and NRSF to nuclei was further confirmed. Valproic acid (VPA), a HDAC4 inhibitor, could reverse the decreased HCN1 and protect neuron damage from OGD/R injury. Collectively, these results demonstrated that I/R cause a decrease of HCN1 expression via enhancing nuclear HDAC4-NRSF gathering and might contribute to neuron damage.