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Neuron-restrictive silencer factor (NRSF), also known as repressor element-1 silencing transcription factor, is a transcriptional repressor that plays important roles in embryonic development and neurogenesis. Recent findings show that NRSF is upregulated after seizures activity however, the link between NRSF and epileptogenesis remains poorly understood. To investigate the role of NRSF in epilepsy, we employed a Cre–loxp system to specifically delete NRSF in excitatory neurons of the postnatal mouse forebrain. In the kindling model of epileptogenesis, conditional NRSF knockout (NRSF-cKO) mice exhibited dramatically accelerated seizure progression and prolonged afterdischarge duration compared with control mice. Moreover, seizures activity–induced mossy fiber sprouting was enhanced in the NRSF-cKO mice. The degree of upregulation of Fibroblast growth factor 14 and Brain-derived neurotrophic factor (BDNF) following kainic acid-induced status epilepticus was significantly increased in the cortex of NRSF-cKO mice compared with control mice. Furthermore, the derepression of BDNF was associated by activation of PLCγ and PI(3)K signaling pathways. These findings indicate that NRSF functions as an intrinsic repressor of limbic epileptogenesis.