The NR4A orphan nuclear receptors mediate transcription-dependent hippocampal synaptic plasticity
Introduction
In the hippocampus, the consolidation of long-term memory (LTM) and the maintenance of long-term potentiation (LTP) both depend on cAMP signaling, PKA activity, gene transcription, and de novo protein synthesis (Abel et al., 1997, Huang and Kandel, 1994, Igaz et al., 2002, Nguyen et al., 1994, Pittenger et al., 2002). A number of transcription factors are known to support activity-driven transcription in neurons, including well-characterized proteins such as cAMP response element-binding protein (CREB) and the immediate early genes C/EBP and Zif268 (see Alberini, 2009 for review). The large family of nuclear receptor transcription factors is increasingly being investigated for its role in memory and plasticity, and the potential of some nuclear receptors to serve as therapeutic targets in disorders of cognition (Hawk and Abel, 2011, Hawk et al., 2012). For example, agonists for the liver X receptor (LXR), retinoic acid receptor (RAR), retinoid X receptor (RXR), and the peroxisome proliferator-activated receptor gamma (PPARγ) have been found to improve memory and synaptic plasticity in mouse models of disease, most notably in models of Alzheimer’s disease (Cramer et al., 2012, Jiang et al., 2008, Pedersen et al., 2006, Wesson et al., 2011).
Although most of the nuclear receptors are regulated by lipophilic ligands that readily cross the nuclear membrane, some are considered “orphan” receptors. These proteins either have no known endogenous ligand, or operate independently of ligand binding. One such group of orphan receptors is the Nr4a subfamily, made up of three closely related members (Nr4a1/Nurr1/NGFI-B, Nr4a2/Nur77/HZF-3, and Nr4a3/NOR-1/TEC) (Hawk and Abel, 2011, Maxwell and Muscat, 2006, Paulsen et al., 1992, Wansa et al., 2003). The NR4A proteins are involved in activity-dependent processes in numerous cell types, supporting such phenomena as apoptosis, metabolism, dopaminergic development, and inflammatory response (for review see Hawk & Abel, 2011). The Nr4a genes are immediate-early genes transcribed rapidly in response to external stimuli (Peña de Ortiz & Jamieson, 1996). Mature NR4A proteins are capable of both positively and negatively regulating the transcription of their downstream targets (Johnson, Michelhaugh, Bouhamdan, Schmidt, & Bannon, 2011), which include plasticity-related genes such as Bdnf1 and Fosl2 (Hawk et al., 2012, Volpicelli et al., 2007).
In many systems, Nr4a transcription is controlled by the cAMP/PKA/CREB signaling pathway (Kovalovsky et al., 2002, Lemberger et al., 2008), which is a cascade critical for transcription of other memory- and plasticity-related genes (Josselyn & Nguyen, 2005). In the hippocampus, training in different behavioral tasks increases the expression of one or all of the Nr4a genes in discrete anatomical regions (Hawk et al., 2012, McNulty et al., 2012, Peña de Ortiz et al., 2000). The induction of long-term potentiation in vivo by high-frequency stimulation (HFS) increases Nr4a gene expression in hippocampal neurons (Dragunow et al., 1996, Ryan et al., 2011), and administration of the GABAA antagonist gabazine enhances excitability and increases Nr4a mRNA levels in hippocampal slices (Pegoraro et al., 2010). Memory enhancement by intrahippocampal administration of the histone deacetylase (HDAC) inhibitor trichostatin A (TSA) further increases the expression of Nr4a1 and Nr4a2 (Vecsey et al., 2007), and knockdown of Nr4a2 attenuates memory enhancement in mice lacking the histone deacetylase HDAC3 (McQuown et al., 2011). Further, disrupting NR4A function by knockout (Rojas, Joodmardi, Hong, Perlmann, & Ogren, 2007), siRNA knockdown (McNulty et al., 2012), antisense oligonucleotides (Colón-Cesario et al., 2006), or expression of a dominant-negative protein (Hawk et al., 2012) impairs learning and long-term memory and blocks memory enhancement by HDAC inhibitors (Hawk et al., 2012). To define the importance of the Nr4a transcription factors in hippocampal synaptic function, we employed a transgenic dominant-negative NR4A protein to inhibit NR4A function. We then measured synaptic function and long-term potentiation at the Schaffer collateral-CA1 synapses. The results presented here support an important role for the NR4A transcription factors in the maintenance of long-term synaptic plasticity, consistent with their role in the consolidation of long-term hippocampus-dependent memory.
Section snippets
Subjects
Mice were maintained under standard conditions consistent with National Institute of Health guidelines for animal care and use and all experimental procedures were approved by the Institutional Animal Care and Use Committee of the University of Pennsylvania. Mice were maintained on a 12:12 light:dark cycle with lights on at 7 AM. Food and water were provided in their home cages ad libitum. Tissue collection and electrophysiological testing were conducted on male and female adult (2–6 months old)
Nr4aDN expression does not change basal synaptic properties
The Nr4a genes are transcribed as immediate-early genes in response to external stimuli such as synaptic activation and in turn they regulate a number of downstream genes, including some involved in synaptic plasticity (Hawk & Abel, 2011). The dominant-negative form of Nr4a expressed in the mutant mice blocks the function of the NR4A proteins, so we began by examining basal synaptic properties to determine if this attenuation of NR4A-mediated transcription caused any disturbances in normal
Discussion
The present study investigated the role of NR4A transcription factor function in LTP in the hippocampus using a dominant-negative NR4A construct to block transactivation by native NR4A proteins (Hawk et al., 2012, Robert et al., 2006). We found that transcription-dependent LTP induced by either spaced high-frequency stimulation or TBS was greatly attenuated in the transgenic mice. However, Nr4aDN expression had no effect on the basal properties of the Schaffer collateral synapses or the
Acknowledgments
We would like to thank Shane Poplawski, Alan Park, Michelle Dumoulin, and Josh Hawk for their comments on the article and the experimental design. This work was supported by predoctoral NRSA fellowship 1F31NS079019 to M. Bridi and NIH Grant R01-MH087463 to T. Abel.
References (51)
- et al.
Genetic demonstration of a role for PKA in the late phase of LTP and in hippocampus-based long-term memory
Cell
(1997) - et al.
Regulation of hippocampus-dependent memory by cyclic AMP-dependent protein kinase
Progress in Brain Research
(2008) - et al.
Activation of NMDA and muscarinic receptors induces nur-77 mRNA in hippocampal neurons
Molecular Brain Research
(1996) - et al.
The role of NR4A transcription factors in memory formation
Brain Research Bulletin
(2011) - et al.
ApoE promotes the proteolytic degradation of Abeta
Neuron
(2008) - et al.
Regulation of histone acetylation during memory formation in the hippocampus
The Journal of Biological Chemistry
(2004) - et al.
Structure-dependent activation of NR4A2 (Nurr1) by 1,1-bis(3′-indolyl)-1-(aromatic)methane analogs in pancreatic cancer cells
Biochemical Pharmacology
(2012) - et al.
The RXR heterodimers and orphan receptors
Cell
(1995) - et al.
Rosiglitazone attenuates learning and memory deficits in Tg2576 Alzheimer mice
Experimental Neurology
(2006) - et al.
Reversible inhibition of CREB/ATF transcription factors in region CA1 of the dorsal hippocampus disrupts hippocampus-dependent spatial memory
Neuron
(2002)
Increasing histone acetylation in the hippocampus-infralimbic network enhances fear extinction
Biological Psychiatry
The AF-1 domain of the orphan nuclear receptor NOR-1 mediates trans-activation, coactivator recruitment, and activation by the purine anti-metabolite 6-mercaptopurine
The Journal of Biological Chemistry
Reduction of dopamine-related transcription factors Nurr1 and NGFI-B in the prefrontal cortex in schizophrenia and bipolar disorders
Schizophrenia Research
Transcription factors in long-term memory and synaptic plasticity
Physiological Reviews
NURR1 mutations in cases of schizophrenia and manic-depressive disorder
American Journal of Medical Genetics
Age-related decreases in Nurr1 immunoreactivity in the human substantia nigra
The Journal of Comparative Neurology
Knockdown of Nurr1 in the rat hippocampus: Implications to spatial discrimination learning and memory
Learning & Memory
ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models
Science
A simple role for BDNF in learning and memory?
Frontiers in Molecular Neuroscience
Identification of a potent agonist of the orphan nuclear receptor Nurr1
ChemMedChem
HDAC inhibition modulates hippocampus-dependent long-term memory for object location in a CBP-dependent manner
Learning & Memory
NR4A nuclear receptors support memory enhancement by histone deacetylase inhibitors
The Journal of Clinical Investigation
Recruitment of long-lasting and protein kinase A-dependent long-term potentiation in the CA1 region of hippocampus requires repeated tetanization
Learning & Memory
Long-lasting forms of synaptic potentiation in the mammalian hippocampus
Learning & Memory
Two time periods of hippocampal mRNA synthesis are required for memory consolidation of fear-motivated learning
The Journal of Neuroscience
Cited by (55)
Role of gene transcription in long-term memory storage
2021, Encyclopedia of Behavioral Neuroscience: Second EditionPharmacological activation of Nr4a rescues age-associated memory decline
2020, Neurobiology of AgingThe α5-GABA <inf>A</inf> R inverse agonist MRK-016 upregulates hippocampal BDNF expression and prevents cognitive deficits in LPS-treated mice, despite elevations in hippocampal Aβ
2019, Behavioural Brain ResearchCitation Excerpt :Nurr1 acts as one of several transcription factors for BDNF, directly influencing learning and memory processes by upregulating BDNF expression [26]. Such increases occur following hippocampus-dependent tasks [27], and disruption of Nurr1 activity in the hippocampus impairs LTP and decreases synaptic plasticity [28]. In the context of inflammation, reports on the specific activity of Nurr1 appear contradictory and are not fully understood, though most of the literature supports the hypothesis that Nurr1 is a negative regulator of inflammation [29,30].
The effect of NR4A1 on APP metabolism and tau phosphorylation
2018, Genes and DiseasesSleep deprivation impairs synaptic tagging in mouse hippocampal slices
2018, Neurobiology of Learning and Memory