To unravel the fundamental mechanisms that fine-tune the level of neuronal excitability, we investigated how transcription factors and repressors are involved in scaling excitability and synaptic transmission. Indeed, epigenetic modifications of chromatin structure have recently emerged as a conserved mechanism by which the nervous system translates external information. The master transcriptional repressor RE1-silencing transcription factor (REST) is a critical regulator of chromatin structure and gene expression, but its precise role in brain physiology and disease is still debated. We focused our attention on the role of REST in scaling excitability and synaptic transmission following sustained hyperexcitation or silencing of neuronal activity (Pozzi et al., 2013; Pecoraro et al., 2017). As REST activity is dysregulated in multiple neurological diseases, including epilepsy and multiple sclerosis, we engineered light-sensitive optogenetic probes that modulate REST activity by illumination (Paonessa et al., 2016). The identification of epigenetic mechanisms and plasticity genes is an issue of high interest in the field of brain plasticity and repair with potential clinical applications in pathological states where a reorganization of neuronal circuitries may be beneficial in adult life. Using the above-mentioned REST-specific optogenetic probe, we are currently addressing the role of the REST in suppressing visual cortical plasticity in the adulthood under physiological conditions and the impact of REST dysregulation in experimental models of epilepsy.