Systematic administration of anti-inflammatory cytokine interleukin 4 (IL-4) has been shown to improve recovery after cerebral ischemic stroke.However,whether IL-4 affects neuronal excitability and how IL-4 improves ischemic injury remain largely unknown.Here we report the neuroprotective role of endogenous IL-4 in focal cerebral ischemia-reperfusion (I/R) injury.In multi-electrode array (MEA)recordings,IL-4 reduces spontaneous firings and network activities of mouse primary cortical neurons.IL-4 mRNA and protein expressions are upregulated after I/R injury.Genetic deletion of Il-4 gene aggravates I/R injury in vivo and exacerbates oxygen-glucose deprivation (OGD) injury in cortical neurons.Conversely,supplemental IL-4 protects Il-4-/-cortical neurons against OGD injury.Mechanistically,cortical pyramidal and stellate neurons common for ischemic penumbra after I/R injury exhibit intrinsic hyperexcitability and enhanced excitatory synaptic transmissions in Il-4-/-mice.Furthermore,upregulation of Nav 1.1 channel,and downregulations of KCa3.1 channel and α6 subunit of GABAA receptors are detected in the cortical tissues and primary cortical neurons from Il-4-/-mice.Taken together,our findings demonstrate that IL-4 deficiency results in neural hyperexcitability and aggravates I/R injury,thus activation of IL-4 signaling may protect the brain against the development of permanent damage and help recover from ischemic injury after stroke.