Restoration of visual cortex plasticity by regulating the transcriptional repressor REST

Sensory experience modifies neuronal networks via the activation of physiological processes that modulate gene transcription. The visual system is a classical paradigm to study how sensory information affects the structural and functional development of the neocortex. Visual cortical plasticity is high in the early postnatal life during the so-called critical period (CP) and becomes constrained over time by the progressive maturation of intracortical inhibition that parallels a reduction of epigenetic mechanisms of transcription. Because of its involvement in epigenetic homeostatic processes, we focused on the Repressor Element 1 (RE1)-Silencing Transcription factor (REST), a transcriptional repressor of a large cluster of neural genes. REST regulates epigenetic mechanisms during nervous system development and homeostatic plasticity in mature neurons by binding to promoter regions of genes that contain the RE1 consensus sites. We show that hampering REST expression can be used to promote the reinstatement of visual cortex plasticity in the adult mouse and the recovery of vision in an adult murine model of amblyopia. The results establish a key role for REST as a homeostatic regulator of cortical plasticity in the adult life, and highlight the potential for REST modulation as a therapeutic approach in neurological disorders where plasticity is compromised.