Through generation of a mouse model with neuron-specific Pnn depletion, we found that Pnn deficiency regulates the expression level of SRSF1 and SRSF2, increases oxidative stress in neurons, and exacerbates ischemia/reperfusion-induced cerebral injury in mice, indicating an important role of Pnn in survival of neurons post ischemic stroke. Here, SRSF2 is linked to ischemic stroke.