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Neuronal restrictive silencing factor (NRSF) is an epigenetic repressor with important role in regulating neurogenesis and differentiation.However, the physiological function of NRSF in postnatal brain remains an interesting question.Here, we reported that activity-dependent synaptic plasticity was suppressed by NRSF.Using cre/ loxP system, nrsfwas conditionally knockout (cko) in forebrain excitatory neurons.Field recording of hippocampus CA1 radiatum area revealed a significantly upregulated long-term potentiation (LTP).We also found that activity stimulation led to significant enhancement of mature BDNF in cko mice, and this enhancement was mediated by the increased level of tissue plasminogen activator (tPA).Moreover, we found tPA was transcriptionally repressed by NRSF through direct binding to RE1 sequence in tPA promoter.Inhibition of tPA activity abolished the upregulation of LTP in nrsf-cko mice.Our findings provide an NRSF mediated epigenetic mechanism that moderates LTP in the hippocampus CA3-CA1 pathway.