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Cell. 2012 Nov 9;151(4):821-834. doi: 10.1016/j.cell.2012.09.037.

HDAC4 governs a transcriptional program essential for synaptic plasticity and memory.

Author information

1
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.
2
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.
3
Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
4
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.

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.

PMID:
23141539
PMCID:
PMC3496186
DOI:
10.1016/j.cell.2012.09.037
[Indexed for MEDLINE]
Free PMC Article

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