title: HDAC4 governs a transcriptional program essential for synaptic plasticity and memory.
abstract: 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.
authors.affiliation: Department of Cell Biology, The Scripps Research Institute, La Jolla, CA 92037, USA; The Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92037, USA; The Kellogg School of Science and Technology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Sando
authors.affiliation: Department of Cell Biology, The Scripps Research Institute, La Jolla, CA 92037, USA; The Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Natalia
authors.initials: N
authors.lastname: Gounko
authors.affiliation: Department of Cell Biology, The Scripps Research Institute, La Jolla, CA 92037, USA; The Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Simon
authors.initials: S
authors.lastname: Pieraut
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Lujian
authors.initials: L
authors.lastname: Liao
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: John
authors.initials: J
authors.lastname: Yates
authors.affiliation: Department of Cell Biology, The Scripps Research Institute, La Jolla, CA 92037, USA; The Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92037, USA. Electronic address: amaximov@scripps.edu.
authors.forename: Anton
authors.initials: A
authors.lastname: Maximov
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D001921:Brain / Q000378:metabolism*; D006655:Histone Deacetylases / Q000378:metabolism*; D008568:Memory; D051379:Mice; D009473:Neuronal Plasticity; D009474:Neurons / Q000378:metabolism*; D016548:Prosencephalon / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013569:Synapses / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D016194:Receptors, N-Methyl-D-Aspartate; D014157:Transcription Factors; C498618:Hdac5 protein, mouse; D006655:Histone Deacetylases