Journal article
Pharmacological Activators of the NR4A Nuclear Receptors Enhance LTP in a CREB/CBP-Dependent Manner
Neuropsychopharmacology (New York, N.Y.), Vol.42(6), pp.1243-1253
05/2017
DOI: 10.1038/npp.2016.253
PMCID: PMC5437882
PMID: 27834392
Abstract
Nr4a nuclear receptors contribute to long-term memory formation and are required for long-term memory enhancement by a class of broad-acting drugs known as histone deacetylase (HDAC) inhibitors. Understanding the molecular mechanisms that regulate these genes and identifying ways to increase their activity may provide novel therapeutic approaches for ameliorating cognitive dysfunction. In the present study, we find that Nr4a gene expression after learning requires the cAMP-response element binding (CREB) interaction domain of the histone acetyltransferase CREB-binding protein (CBP). These gene expression deficits emerge at a time after learning marked by promoter histone acetylation in wild-type mice. Further, mutation of the CREB-CBP interaction domain reduces Nr4a promoter acetylation after learning. As memory enhancement by HDAC inhibitors requires CREB-CBP interaction and Nr4a gene function, these data support the notion that the balance of histone acetylation at the Nr4a promoters is critical for memory formation. NR4A ligands have recently been described, but the effect of these drugs on synaptic plasticity or memory has not been investigated. We find that the 'C-DIM' NR4A ligands, para-phenyl substituted di-indolylmethane compounds, enhance long-term contextual fear memory and increase the duration of long-term potentiation (LTP), a form of hippocampal synaptic plasticity. LTP enhancement by these drugs is eliminated in mice expressing a dominant negative form of NR4A and attenuated in mice with mutation of the CREB-CBP interaction domain. These data define the molecular connection between histone acetylation and Nr4a gene expression after learning. In addition, they suggest that NR4A-activating C-DIM compounds may serve as a potent and selective means to enhance memory and synaptic plasticity.
Details
- Title: Subtitle
- Pharmacological Activators of the NR4A Nuclear Receptors Enhance LTP in a CREB/CBP-Dependent Manner
- Creators
- Morgan S Bridi - Mahoney Institute for Neurosciences, University of Pennsylvania, Philadelphia, PA, USAJoshua D Hawk - Mahoney Institute for Neurosciences, University of Pennsylvania, Philadelphia, PA, USASnehajyoti Chatterjee - Smilow Center for Translational Research, Department of Biology, University of Pennsylvania, Philadelphia, PA, USAStephen Safe - Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX, USATed Abel - Smilow Center for Translational Research, Department of Biology, University of Pennsylvania, Philadelphia, PA, USA
- Resource Type
- Journal article
- Publication Details
- Neuropsychopharmacology (New York, N.Y.), Vol.42(6), pp.1243-1253
- Publisher
- England
- DOI
- 10.1038/npp.2016.253
- PMID
- 27834392
- PMCID
- PMC5437882
- ISSN
- 0893-133X
- eISSN
- 1740-634X
- Grant note
- R01 MH087463 / NIMH NIH HHS
- Language
- English
- Date published
- 05/2017
- Academic Unit
- Molecular Physiology and Biophysics; Psychiatry; Psychological and Brain Sciences; Iowa Neuroscience Institute; Neuroscience and Pharmacology; Biochemistry and Molecular Biology
- Record Identifier
- 9984070895102771
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