1. NR4A nuclear receptors support memory enhancement by histone deacetylase inhibitors.
- Author
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Hawk JD, Bookout AL, Poplawski SG, Bridi M, Rao AJ, Sulewski ME, Kroener BT, Manglesdorf DJ, and Abel T
- Subjects
- Animals, Avoidance Learning drug effects, Avoidance Learning physiology, Conditioning, Operant drug effects, Conditioning, Operant physiology, Cyclic AMP Response Element-Binding Protein metabolism, Electroshock, Fear physiology, Freezing Reaction, Cataleptic drug effects, Freezing Reaction, Cataleptic physiology, Gene Expression Regulation drug effects, Genes, Dominant, Hippocampus metabolism, Histone Deacetylase Inhibitors therapeutic use, Memory Disorders chemically induced, Memory Disorders genetics, Memory Disorders prevention & control, Memory, Long-Term drug effects, Memory, Short-Term drug effects, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Nerve Tissue Proteins agonists, Nerve Tissue Proteins biosynthesis, Nerve Tissue Proteins genetics, Nootropic Agents therapeutic use, Nuclear Receptor Subfamily 4, Group A, Member 1 deficiency, Nuclear Receptor Subfamily 4, Group A, Member 1 genetics, Nuclear Receptor Subfamily 4, Group A, Member 1 physiology, Nuclear Receptor Subfamily 4, Group A, Member 2 physiology, Orphan Nuclear Receptors biosynthesis, Orphan Nuclear Receptors genetics, Phosphorylation drug effects, Protein Processing, Post-Translational drug effects, Transcription Factors agonists, Histone Deacetylase Inhibitors pharmacology, Memory, Long-Term physiology, Nerve Tissue Proteins physiology, Nootropic Agents pharmacology, Orphan Nuclear Receptors physiology, Transcription Factors physiology
- Abstract
The formation of a long-lasting memory requires a transcription-dependent consolidation period that converts a short-term memory into a long-term memory. Nuclear receptors compose a class of transcription factors that regulate diverse biological processes, and several nuclear receptors have been implicated in memory formation. Here, we examined the potential contribution of nuclear receptors to memory consolidation by measuring the expression of all 49 murine nuclear receptors after learning. We identified 13 nuclear receptors with increased expression after learning, including all 3 members of the Nr4a subfamily. These CREB-regulated Nr4a genes encode ligand-independent "orphan" nuclear receptors. We found that blocking NR4A activity in memory-supporting brain regions impaired long-term memory but did not impact short-term memory in mice. Further, expression of Nr4a genes increased following the memory-enhancing effects of histone deacetylase (HDAC) inhibitors. Blocking NR4A signaling interfered with the ability of HDAC inhibitors to enhance memory. These results demonstrate that the Nr4a gene family contributes to memory formation and is a promising target for improving cognitive function.
- Published
- 2012
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