Class IIa HDACs regulate learning and memory through dynamic experience-dependent repression of transcription

Abstract

The formation of new memories requires transcription. However, the mechanisms that limit signaling of relevant gene programs in space and time for precision of information coding remain poorly understood. We found that, during learning, the cellular patterns of expression of early response genes (ERGs) are regulated by class IIa HDACs 4 and 5, transcriptional repressors that transiently enter neuronal nuclei from cytoplasm after sensory input. Mice lacking these repressors in the forebrain have abnormally broad experience-dependent expression of ERGs, altered synaptic architecture and function, elevated anxiety, and severely impaired memory. By acutely manipulating the nuclear activity of class IIa HDACs in behaving animals using a chemical-genetic technique, we further demonstrate that rapid induction of transcriptional programs is critical for memory acquisition but these programs may become dispensable when a stable memory is formed. These results provide new insights into the molecular basis of memory storage. The molecular mechanisms of memory storage remain poorly understood. In this study, authors describe a new mechanism that regulates the cellular patterns of early response gene signaling during learning via the recruitment of two functionally redundant nuclear repressors, class IIa histone deacetylases (HDACs) 4 and 5