HDAC4 Governs a Transcriptional Program Essential for Synaptic Plasticity and Memory

Neuronal activity influences genes involved in circuit development and information processing. However, the molecular basis of this process remains poorly understood. We found that HDAC4, a histone deacetylase that shuttles between the nucleus and cytoplasm, controls a transcriptional program essential for synaptic plasticity and memory. The nuclear import of HDAC4 and its association with chromatin is negatively regulated by NMDA receptors. In the nucleus, HDAC4 represses genes encoding constituents of central synapses, thereby affecting synaptic architecture and strength. Furthermore, we show that a truncated form of HDAC4 encoded by an allele associated with mental retardation is a gain-of-function nuclear repressor that abolishes transcription and synaptic transmission despite the loss of the deacetylase domain. Accordingly, mice carrying a mutant that mimics this allele exhibit deficits in neurotransmission, spatial learning, and memory. These studies elucidate a mechanism of experience-dependent plasticity and define the biological role of HDAC4 in the brain. [Display omitted] ► HDAC4 is a histone deacetylase that shuttles between the nucleus and cytoplasm ► HDAC4 associates with neuronal chromatin and TFs in an NMDA receptor-dependent manner ► HDAC4 represses genes essential for synaptic function ► HDAC4 regulates synaptic transmission and memory without deacetylating histones Neuronal activity triggers the nuclear export of HDAC4, which in turn induces genes that regulate circuit development and information processing. Misregulation of this pathway in mice impairs neurotransmission, spatial learning, and memory.