NR4A nuclear receptors support memory enhancement by histone deacetylase inhibitors
Joshua D. Hawk, … , David J. Manglesdorf, Ted Abel
Joshua D. Hawk, … , David J. Manglesdorf, Ted Abel
Published September 10, 2012
Citation Information: J Clin Invest. 2012;122(10):3593-3602. https://doi.org/10.1172/JCI64145.
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Research Article Neuroscience

NR4A nuclear receptors support memory enhancement by histone deacetylase inhibitors

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.

Authors

Joshua D. Hawk, Angie L. Bookout, Shane G. Poplawski, Morgan Bridi, Allison J. Rao, Michael E. Sulewski, Brian T. Kroener, David J. Manglesdorf, Ted Abel

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Figure 2

Blocking function of NR4A family NRs in the hippocampus impairs long-term memory formation.

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Blocking function of NR4A family NRs in the hippocampus impairs long-ter...
(A) To impede NR4A signaling in forebrain neurons, a tTA transgene expressed selectively in the forebrain was used to activate a dominant-negative Nr4a transgene (NR4ADN) under control of the tetO. (B) An antibody to the YFP tag on the transgenic NR4ADN protein coimmunoprecipitates endogenous NR4A2 protein from hippocampal protein extracts, confirming the ability of the dominant-negative transgenic protein to heterodimerize with NR4A protein. (C) In the top row, immunolabeling for the NR4ADN hemagglutinin (HA) tag (brown) with cresyl violet counterstain (purple) shows expression in the hippocampus as well as in cortex and striatum (original magnification, ×100). Fluorescent immunolabeling for the YFP tag (middle row) and propidium iodide counterstaining (bottom row) illustrates transgene expression in hippocampal subregions CA1 (original magnification, ×250) and the dentate gyrus (DG) (original magnification, ×250) but not the amygdala (original magnification, ×62.5). (D) NR4ADN mice have selective deficits in long-term contextual fear memory, whereas neither short-term contextual nor long-term cued fear conditioning are impaired. (E) No difference in 24-hour contextual fear memory performance was detected between wild-type and NR4ADN mice after 4 weeks of doxycycline (dox) treatment (P = 0.87, n = 12 mice/group). All error bars denote SEM. *P < 0.05. See also Supplemental Figure 2.