Neurological disorders may be inherited, but can also be acquired through injury or other environmental factors. Understanding the mechanisms behind the acquisition of neurological disorders may give us insight into the disease process as well as into the fundamentals of neuroplasticity. Persistent alteration of the expression of a large number of genes is often a hallmark of acquired brain pathologies. The transcriptional repressor neuron-restrictive silencer factor (NRSF) has been shown to induce large-scale, coordinate changes in gene expression. Therefore, the role of NRSF in neuroplasticity and disease was investigated. First, NRSF was examined in the context of an acquired epilepsy model. NRSF expression levels were augmented after an insult that leads to epilepsy, and additionally there was a repression of the expression levels of a putative NRSF-regulated gene, hcn1, that is important in the development of epilepsy. It was also observed that NRSF binds with hcn1. Blocking the function of NRSF after the insult that led to epilepsy attenuated the development of the disease. The mechanism by which NRSF repressed hcn1 expression involved an increase in binding to the gene, and blocking NRSF binding rescued hcn1 from repression. NRSF led to epigenetic changes in the chromatin, and these changes may underlie the enduring repression of hcn1 expression. Other genes, in addition to hcn1, were rescued by blocking NRSF function after an insult that leads to epilepsy. The moderate affinity of these genes to NRSF enabled them to be dynamically regulated by varying cellular levels of NRSF. It was also discovered that NRSF may play a role in a stress-related disease model that is characterized by persistent changes in the expression of another putative NRSF-regulated gene, crh. Together, these findings point to neuroplasticity of gene expression as a potent mechanism in brain pathology, and may lead to the development of breakthrough therapeutics for many neurological disorders.