REVIEW published: 22 November 2021 doi: 10.3389/fnmol.2021.786226 Nr4a2 Transcription Factor in Hippocampal Synaptic Plasticity, Memory and Cognitive Dysfunction: A Perspective Review Judit Català-Solsona 1,2 , Alfredo J. Miñano-Molina 1,2 and José Rodríguez-Álvarez 1,2,3* 1 Departament de Bioquímica i Biologia Molecular, Institut de Neurociències, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain, 2 Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain, 3 Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, New York, NY, United States Long-lasting changes of synaptic efficacy are largely mediated by activity-induced gene transcription and are essential for neuronal plasticity and memory. In this scenario, Edited by: transcription factors have emerged as pivotal players underlying synaptic plasticity and Toh Hean Ch’ng, the modification of neural networks required for memory formation and consolidation. Nanyang Technological University, Singapore Hippocampal synaptic dysfunction is widely accepted to underlie the cognitive decline Reviewed by: observed in some neurodegenerative disorders including Alzheimer’s disease. Therefore, Timothy J. Jarome, understanding the molecular pathways regulating gene expression profiles may help to Virginia Tech, United States Minho Moon, identify new synaptic therapeutic targets. The nuclear receptor 4A subfamily (Nr4a) of Konyang University, South Korea transcription factors has been involved in a variety of physiological processes within *Correspondence: the hippocampus, ranging from inflammation to neuroprotection. Recent studies have José Rodríguez-Álvarez also pointed out a role for the activity-dependent nuclear receptor subfamily 4, group jose.rodriguez@uab.es A, member 2 (Nr4a2/Nurr1) in hippocampal synaptic plasticity and cognitive functions, Specialty section: although the underlying molecular mechanisms are still poorly understood. In this review, This article was submitted to Molecular Signalling and Pathways, we highlight the specific effects of Nr4a2 in hippocampal synaptic plasticity and memory a section of the journal formation and we discuss whether the dysregulation of this transcription factor could Frontiers in Molecular Neuroscience contribute to hippocampal synaptic dysfunction, altogether suggesting the possibility Received: 29 September 2021 that Nr4a2 may emerge as a novel synaptic therapeutic target in brain pathologies Accepted: 27 October 2021 Published: 22 November 2021 associated to cognitive dysfunctions. Citation: Keywords: Nr4a2, transcription factor, hippocampus, synaptic plasticity, brain, learning, memory Català-Solsona J, Miñano-Molina AJ and Rodríguez-Álvarez J (2021) Nr4a2 Transcription Factor in Hippocampal INTRODUCTION Synaptic Plasticity, Memory and Cognitive Dysfunction: Nuclear receptor subfamily 4, group A (Nr4a), which belongs to the nuclear receptor superfamily, A Perspective Review. consists in a family of three close-related immediate early genes that encode three orphan nuclear Front. Mol. Neurosci. 14:786226. receptors (Nr4a1/NGFI-B, Nr4a2/Nurr1, and Nr4a3/NOR-1). They are expressed in a wide variety doi: 10.3389/fnmol.2021.786226 of metabolically demanding and energy dependent tissues, such as skeletal muscle, adipose tissue, Frontiers in Molecular Neuroscience | www.frontiersin.org 1 November 2021 | Volume 14 | Article 786226 Català-Solsona et al. Nr4a2, Synaptic Plasticity and Memory heart, kidney, T-cells, liver and distinct but overlapping regions N-terminal domain (NTD), a conserve DNA-binding domain of the brain (Zetterström et al., 1996). The three members exhibit (DBD) and a ligand-binding domain (LBD) containing its tissue-specific expression and hence their roles are context as well transactivation-dependent AF-2 in the C-terminal domain as tissue-specific. (CTD) (Ichinose et al., 1999). Classically, nuclear receptor Nr4a proteins function as transcription factors that recognize activation is accomplished by the binding of a lipophilic ligand DNA response elements to regulate the expression of a variety in a hydrophobic pocket within the LBD. By contrast, the crystal of genes involved in multiple biological processes including structure of Nr4a2 reveals that the Nr4a2-LBD lacks a classical proliferation, metabolism, immunity, cellular stress, apoptosis, biding pocket for coactivators and/or ligands because of the tight DNA repair, and angiogenesis (Safe et al., 2016). Nr4a activity packing of side chains from several bulky hydrophobic side- depends not only on its transcriptional levels (including miRNA chain residues, adopting a canonical protein fold resembling targeting) but also on alternative splicing, post-translational that of an agonist-bound, transcriptionally active LBD (Wang modifications, subcellular localization and interaction with et al., 2003). Thus, it is believed that a major difference other nuclear receptors (Maxwell and Muscat, 2006). These between Nr4a2 and classical nuclear receptors is the absence of transcriptional regulators may be stably expressed or induced endogenous ligand regulation. Therefore, Nr4a2 activity will be as immediate early genes in response to a wide range of regulated at the level of gene expression and protein stability physiological signals, including synaptic activity (Pegoraro et al., (Maxwell and Muscat, 2006). Nevertheless, during the last 2010). The ability to sense and rapidly respond to changes in the years, several studies have identified synthetic ligands, known cellular environment appears to be a hallmark of this subfamily as Nr4a2 agonists, which can modulate Nr4a2 transcriptional of orphan nuclear receptors. function (Hammond et al., 2015; Kim et al., 2015; Chatterjee In peripheral tissues, these receptors have been involved in the et al., 2020). Identification of such Nr4a2 agonists triggered onset and progression of various types of cancer, inflammation, the possibility of a pharmacological therapeutic approach for atherosclerosis and obesity (Ranhotra, 2015). Notably, Nr4a diseases related to Nr4a2 (Skerrett et al., 2014; Kim et al., 2015; transcription factors have also emerged as essential mediators Moon et al., 2019; Chatterjee et al., 2020; Jeon et al., 2020). in several physio-pathological situations in the central nervous The canonical view of Nr4a2 as an orphan nuclear receptor system (CNS). The Nr4a family of transcriptional regulators has has been recently challenged by some studies showing that the been reported to modulate hippocampal synaptic plasticity and Nr4a2-LBD is highly dynamic with solvent accessibility and hippocampal-dependent memory (Hawk and Abel, 2011; Bridi the capability to expand (de Vera et al., 2019) allowing the and Abel, 2013) and the alteration of expression or function of binding of putative endogenous ligands (Bruning et al., 2019; these factors has been associated to neurodegenerative diseases Rajan et al., 2020). (Skerrett et al., 2014), intellectual disability such as autism Nr4a2 protein regulates both positively and negatively the (Chuang et al., 2015), schizophrenia (Rojas et al., 2007; Ruiz- transcription of its target genes by directly binding to response Sánchez et al., 2021) and epilepsy (Zhang et al., 2016). elements in their promoters. Two zinc fingers of the highly This review will primarily focus on the current knowledge conserved Nr4a2-DBD as a monomer or homodimer can bind about Nr4a2 contribution to the active-dependent processes the nerve growth factor-inducible-β-binding response element that underlie synaptic plasticity, learning and memory and the (NBRE; 50 -AAAGGTCA-30 ) or as homodimer or heterodimer evidence supporting a critical role of this factor in several brain with Nr4a1 can attach to the Nur response element (NurRE; pathologies associated to cognitive dysfunction. 50 -TGACCTTT-N6-AAAGGTCA-30 ). Moreover, as monomer, homodimer or heterodimer, Nr4a2 can dimerize with the retinoic X receptor (RXR) and bind to a motif referred to as DR5 Nr4a2 TRANSCRIPTION FACTOR (Figure 1B). This union is permissive; meaning that ligand binding of RXR typically causes full activation of the entire Nuclear receptor subfamily 4, group A, member 2 (Nr4a2), heterodimer (Jiang et al., 2019). which belongs to the Nr4a subfamily of transcription factors, Nr4a2 is known to be a key regulator of the midbrain is primarily expressed in neurons of diverse areas of the dopaminergic neurons differentiation, maintenance and survival CNS, particularly in the substantia nigra pars compacta, (Saucedo-Cardenas et al., 1998; Sousa et al., 2007; Jo et al., ventral tegmental area and limbic area (Zetterström et al., 2009), being responsible for the transcription of several genes 1996). Moreover, it is also expressed in the hippocampus, involved in the dopaminergic neuronal phenotype, ranging subiculum, temporal cortex, olfactory bulb, cerebellum, posterior from genes regulating dopaminergic metabolism, differentiation hypothalamus, and habenuclear nuclei (Saucedo-Cardenas and and neurotransmission (tyrosine hydroxylase –TH–, vesicular Conneely, 1996; Quina et al., 2009). Nevertheless, Nr4a2 is amine transporter 2 –VMAT–, dopamine transporter –DAT– expressed not only in neurons, but also in non-neuronal cells ), mitochondrial function (sodium oxide dismutase 1 –SOD1–, such as microglia, astrocytes or endothelial cells (Fan et al., 2009; Ts translation elongation factor mitochondrial –TSFM–, cyclo- Saijo et al., 2009) and it is found not only in the CNS but also in oxigenase 5β –COX5β–) and dopaminergic neuronal survival other tissues, including the bone, synovial tissues, adrenal gland (Ret) (Kadkhodaei et al., 2009; Decressac et al., 2013). In or the intestine. dopaminergic neurons, Nr4a2 also has an essential role in the Nr4a2 structure (Figure 1A) is composed by a modulator neuroprotection and anti-inflammatory responses after exposure domain, referred to as the activation function (AF-1) or the to neuropathological stress or insults. It has been reported Frontiers in Molecular Neuroscience | www.frontiersin.org 2 November 2021 | Volume 14 | Article 786226 Català-Solsona et al. Nr4a2, Synaptic Plasticity and Memory FIGURE 1 | Nr4a2 structure and binding to target genes. (A) Structural domains of Nr4a2, which include NTD, DBD and LBD. Modulator domains (AF-1 and AF-2) and localization signals (NLS and NES) are also depicted. (B) Nr4a2 DNA-binding sites as monomers at NBRE sites, as dimers (homodimers or heterodimers, not shown) at NurRE sites and as heterodimers with RXR at DR5 sites. AF, activation function; CTD, C-terminal domain; DBD, DNA-binding domain; LBD, ligand-binding domain, NBRE, nerve growth factor-inducible-β-binding response element; NES, nuclear export signal; NLS, nuclear localization signal, NTD, N-terminal domain; NurRE, nur-response element; RXR, retinoic X receptor. that Nr4a2-null heterozygous dopaminergic neurons exhibit modulates transcription of Nr4a2 (Volakakis et al., 2010; greater vulnerability to neurotoxins (Le et al., 1999). Importantly, Barneda-Zahonero et al., 2012) has fostered the interest for Nr4a2 protects dopaminergic neurons from neuroinflammation studying the putative role of Nr4a2 in synaptic plasticity and insults not only through its function in neurons, but also learning and memory processes. glial cells (Bensinger and Tontonoz, 2009), since it is able to suppress inflammatory gene expression in microglia and astrocytes through transcriptional repression of the NFκB ROLE OF Nr4a2 IN HIPPOCAMPAL transcription factor, essential to induce inflammatory responses SYNAPTIC PLASTICITY, LEARNING, AND (Saijo et al., 2009). MEMORY Nr4a2 contains a “half-CRE” site in its promoter, being controlled by the CREB signaling pathway in many systems, Several reports have highlighted a role for the Nr4a family including the hippocampus, which is a cascade critical for of transcription factors in hippocampal synaptic plasticity and the transcription of diverse plasticity- and memory-related cognitive functions and there is an overwhelming amount of genes (Volakakis et al., 2010; Barneda-Zahonero et al., 2012). evidence showing that synaptic plasticity is a fundamental Although CREB binds with higher affinity to the full 8-base mechanism contributing to learning and memory storage consensus CRE site, it also binds to several variations of this (Martin et al., 2000; Abraham et al., 2019). Studies revealing sequence, including the so-called “half-CRE” site (50 CGTCA-30 the implication of the Nr4a family of transcription factors in and 50 -TGACG-30 ), which may be found in many promoters hippocampal synaptic plasticity have supported a putative role of CREB target genes including Nr4a2 (Zhang et al., 2005). of these factors in learning and memory formation (Hawk and CREB has been extensively studied in the brain since it is Abel, 2011). Early studies showed an increase in Nr4a1 mRNA involved in a variety of relevant processes such as learning in CA1 after contextual fear conditioning during consolidation and memory or neuronal survival, among others (Benito and (von Hertzen and Giese, 2005; Keeley et al., 2006). Later, it was Barco, 2015). For example, it is known that CREB activity is found that expression of a dominant-negative form of Nr4a in crucial for the maintenance of long-term plasticity and memory the mouse forebrain, including the hippocampus, impaired long- formation (Bourtchuladze et al., 1994; Bartsch et al., 1998; term hippocampus-dependent contextual fear memory without Kaldun and Sprecher, 2019). Moreover, the genetic program affecting short-term contextual fear memory or hippocampus- downstream CREB is complex and different transcriptional independent cued fear memory (Hawk et al., 2012). Furthermore, programs could be elicited depending on the triggering stimulus, it was also observed that histone deacetylase (HDAC) inhibitors- cellular context, and upstream signaling events (Nonaka et al., mediated memory enhancement was accompanied by an 2014). Furthermore, selective gene transcription by CREB is increase in the expression of Nr4a family members meanwhile highly modulated by the recruitment of specific coactivators blocking Nr4a family expression in the hippocampus prevented such as the CREB binding protein (CBP/p300) or CREB HDAC inhibitors-mediated improvement of long-term memory regulated Transcription Coactivator (CRTC1 and CRTC2) (Hawk et al., 2012). Supporting the role of Nr4a transcription (Altarejos and Montminy, 2011). Reports showing that CREB factors in hippocampal synaptic plasticity associated to learning Frontiers in Molecular Neuroscience | www.frontiersin.org 3 November 2021 | Volume 14 | Article 786226 Català-Solsona et al. Nr4a2, Synaptic Plasticity and Memory and memory, a strongly impaired transcription-dependent deleted in the CA1 area of the mice dorsal hippocampus hippocampal long-term potentiation (LTP) maintenance of (McQuown et al., 2011). Schaffer collateral to CA1 synapses was observed in hippocampal Cognitive decline is also associated with aging and Nr4a2 slices from Nr4a dominant negative mutant mice whereas expression gradually decreases in the gerbil hippocampus with no deficits in basal synaptic transmission were observed increasing age (Ahn et al., 2018). Furthermore, Nr4a2 has (Bridi and Abel, 2013). also been recently related to long-term memory impairments Both hippocampal LTP and long-term memory are enhanced in aged animals (Kwapis et al., 2019). Whereas adult or by the pharmacological inhibition or genetic ablation of HDAC aged rats with intact cognitive functions showed an increase enzymes, which increase histone acetylation in a CREB- in Nr4a2 expression in the dorsal hippocampus after the dependent manner (Vecsey et al., 2007). Importantly, HDAC object recognition memory training, Nr4a2 failed to be inhibition failed to enhance LTP in hippocampal slices from induced in the cognitively impaired aged rats. Learning- Nr4a dominant negative mutant mice, indicating that Nr4a induced Nr4a2 was also impaired in the hippocampus of aging transcription factors are necessary for mediating the effects of mice. Thus, a cross-species impairment of Nr4a2 hippocampal HDAC inhibition on synaptic plasticity (Bridi and Abel, 2013). expression is observed in mice and rats with cognitive deficits. Although these results supported the importance of the Interestingly, failed induction of Nr4a2 expression is reversed Nr4a family members for hippocampal memory formation, when HDAC3 is deleted in the dorsal hippocampus. Deletion it is still uncertain which are the specific role for each of HDAC3 or hippocampal overexpression of Nr4a2 were able member: Nr4a1, Nr4a2, and Nr4a3. A differential role in to ameliorate object location memory impairment in aged mice learning for Nr4a1 and Nr4a2 was reported by McNulty and (Kwapis et al., 2019). co-workers (McNulty et al., 2012). Using small interfering Indeed, Nr4a2 has also been described to play a role RNA (siRNA), they found that downregulation of Nr4a2 in hippocampal neurogenesis and increasing evidence exists disrupted long-term memory in the object location and supporting that neurogenesis in the sub granular zone of object recognition tasks whereas Nr4a1 seemed to be only the hippocampus could play a key role in long-term spatial required for object location memory. Bridi and co-workers memory. Interestingly, Nr4a2 is abundantly expressed in adult reported an enhancement of LTP when hippocampal slices hippocampal neural precursor cells and it stimulates their were incubated with Nr4a1 activators, para-phenyl substituted proliferation and differentiation both in vitro and in vivo (Kim di-indolylmethane compounds or DIM-C (Bridi et al., 2017). et al., 2016). Thus, Nr4a2 could have an important role in DIM-C-pPhOCH3 or DIM-C-pPhBr enhanced LTP at the CA3– hippocampal learning and memory not only by a functional CA1 hippocampal synapses. This enhancement was absent when modulation of synaptic plasticity but also by acting through LTP was triggered in slices from dominant-negative Nr4a mice. hippocampal neurogenesis. Several studies have evaluated the role of Nr4a2 in memory Although a great deal of evidence has highlighted a acquisition and consolidation, reporting an increase in the role for Nr4a2 in hippocampal-dependent cognitive functions hippocampal expression of Nr4a family members after learning (Table 1), the underlying molecular mechanisms are still poorly of hippocampus-dependent tasks. A specific increase of Nr4a2 understood. Nr4a2 is induced by neuronal activity and its in the hippocampus was observed after different memory- expression is mainly dependent on CREB/CRTC1 and calcium inducing activities. Acquisition of a spatial food search task channels activation (España et al., 2010; Parra-Damas et al., in adult rats produced an increase in the levels of Nr4a2 2014, 2017a,b; Tokuoka et al., 2014). However, knowledge of mRNA in CA1 and CA3 subregions of the dorsal hippocampus the molecular pathways involved in Nr4a2 function in synaptic (Peña de Ortiz et al., 2000) and the injection of antisense plasticity in the hippocampus is still incomplete. It is known oligodeoxynucleotides targeting Nr4a2 in the CA3 hippocampal that Nr4a2 transcription factor regulates several genes implicated area impaired long-term memory and reversal learning in an in hippocampal synaptic plasticity and memory formation appetitive spatial learning task (Colón-Cesario et al., 2006). (Volpicelli et al., 2007; Hawk et al., 2012; Kim et al., 2020). One Relatedly, contextual fear conditioning increased Nr4a2 mRNA example is Fosl2, a member of the AP-1 family of transcription and promoter acetylation in a CREB/CBP-dependent manner factors, a family that is known to be important for memory (Vecsey et al., 2007; Bridi et al., 2017; Oliveira et al., 2018). storage (Fleischmann et al., 2003). Other intriguing Nr4a2 target The role of Nr4a2 in other hippocampal-dependent behavioral genes include two receptor protein tyrosine phosphatases, a tasks like passive avoidance was also reported when Nr4a2 class of molecules implicated in excitatory synapse formation heterozygous mice showed reduced ability to form long-term (Dunah et al., 2005) and the myristoylated alanine-rich C emotional memories (Rojas et al., 2007). Also, deep brain kinase substrate (MARCKS), which can modulate memory stimulation in rats by intracranial self-stimulation treatment formation (McNamara et al., 2005). Of particular interest as immediately after the acquisition session of a two-way active a candidate target gene by which Nr4a2 influences synaptic avoidance conditioning showed both increased Nr4a2 protein plasticity and memory is BDNF, a neurotrophic factor that levels in the hippocampus and improved retention (Aldavert- regulates synaptic plasticity (Zagrebelsky and Korte, 2014) and Vera et al., 2013). Accordingly with the above-commented contributes to the formation and long-term persistence of results observed with HDAC inhibitors, it was also reported that hippocampus-dependent memories (Bekinschtein et al., 2014; a Nr4a2-dependent enhancement of novel object recognition Miranda et al., 2019). Nr4a2 transcriptional activity regulates long-term memory was observed when HDAC3 expression was BDNF levels in different systems. Volpicelli et al. (2007) Frontiers in Molecular Neuroscience | www.frontiersin.org 4 November 2021 | Volume 14 | Article 786226 Català-Solsona et al. Nr4a2, Synaptic Plasticity and Memory TABLE 1 | Overview of the overall effects of Nr4a2 in hippocampal synaptic plasticity, learning and memory. Nr4a2 effects in hippocampal synaptic plasticity, learning and memory References Changes in hippocampal Nr4a2 expression after memory-inducing activities Increase in Nr4a2 mRNA in CA1 and CA3 after acquisition of a spatial food search task in adult rats Peña de Ortiz et al., 2000 Increase in hippocampal Nr4a2 mRNA and promoter acetylation after contextual fear conditioning in a CREB/CBP-dependent Vecsey et al., 2007 manner in mice Oliveira et al., 2018 Bridi et al., 2017 Increase in Nr4a2 protein levels with intracranial self-stimulation treatment after the acquisition session of a two-way active Aldavert-Vera et al., 2013 avoidance test in rats Failure in Nr4a2 increase in the dorsal hippocampus in cognitively impaired aged rats after object recognition memory training Kwapis et al., 2019 Impaired hippocampal learning and memory in absence of Nr4a2 Nr4a2 siRNA disrupts long-term memory in the object location and object recognition tasks McNulty et al., 2012 Injection of Nr4a2 antisense oligodeoxynucleotides in the CA3 area impairs long-term memory and reversal learning in an Colón-Cesario et al., 2006 appetitive spatial learning task Nr4a2 heterozygous mice show reduced ability to form long-term emotional memories in the passive avoidance task Rojas et al., 2007 The enhancement of location-dependent and novel object recognition long-term memory with HDAC deletion in hippocampal McQuown et al., 2011 CA1 is specifically abolished by intrahippocampal delivery of Nr4a2 siRNA Improved hippocampal learning and memory with Nr4a2 overexpression Hippocampal overexpression of Nr4a2 ameliorates the impairment in object location memory in aged mice Kwapis et al., 2019 Nr4a2 regulates hippocampal neurogenesis Nr4a2 stimulates the proliferation and differentiation of adult hippocampal neural precursor cells both in vitro and in vivo Kim et al., 2016 Nr4a2 regulates genes involved in hippocampal synaptic plasticity and memory formation Fosl2 Fleischmann et al., 2003 Receptor protein tyrosine phosphatases Dunah et al., 2005 Myristoylated alanine-risch C kinase substrate (MARCKS) McNamara et al., 2005 BDNF In rat midbrain neurons Volpicelli et al., 2007 In cerebellar granule cells Barneda-Zahonero et al., 2012 In rat microglia Chen et al., 2018 have shown that Nr4a2 regulates Bdnf gene expression in the phosphorylated state of transcription factors and their rat midbrain neurons and similar results were also reported cytosol-nuclear localization (Klann and Dever, 2004). However, in cerebellar granule cells (Barneda-Zahonero et al., 2012) the view that activity-dependent transcriptional regulation and in activated rat microglia overexpressing Nr4a2 (Chen is based on post-translational modification of transcription et al., 2018). Moreover, BDNF was early on implicated in factors located in the cytosol or nucleus is changing. Several modulating neuronal activity, and its own production and transcription modulators involved in learning and memory, release has been shown to be activity-dependent (Kovács et al., such as CRTCs, NFκB or HDAC4, have been reported to 2007; Parra-Damas et al., 2014). However, relatively little is be located at synapses and to be transported to nucleus known about the mechanisms underlying the activity-dependent upon synapse stimulation (Uchida and Shumyatsky, 2018). regulation of BDNF expression. Future studies are needed for CRTC1 has been found in the postsynaptic density (PSD) a fully comprehensive knowledge of the cellular and molecular subfraction obtained from adult mouse brain and in excitatory mechanisms involved in the role of Nr4a2 in hippocampal synapses from hippocampal cultures. It translocates to nucleus synaptic plasticity, learning, and memory. in response to localized synaptic activity or induction of LTP (Ch’ng Toh et al., 2012). Histone deacetylase 4 (HDAC4) shuttles between the cytosol and the nucleus in response to IS Nr4a2 A SYNAPTONUCLEAR neuronal activity. Although HDAC4 is mainly located in the PROTEIN MESSENGER? neuronal cytoplasm with a more variable nuclear presence, immunohistochemistry studies have shown a strong PSD Long-term memory involves persistent changes in synaptic immunoreactivity in dendritic spines (Darcy et al., 2010). proteome and structure that require the regulation of gene Another transcriptional modulator with a synaptic localization transcription (Alberini, 2009; Heo et al., 2018). Transcription is NFκB (Kaltschmidt et al., 1993; Meffert et al., 2003), factors involved in learning and memory will translocate in which is activated upon depolarization (Meffert et al., 2003). and out the nucleus in response to the signaling cascades Other transcriptional modulators are known to be present at activated at synapses (Ch’ng and Martin, 2011). Several pathways, synapses, such as Arc and ATF2 (Lai et al., 2008; Shepherd typically requiring calcium signaling, have been described to and Bear, 2011) and it is likely that the list of transcriptional connect synaptic inputs to gene transcription (Hagenston and regulators that participate in synapse to nucleus signaling will Bading, 2011). Activation of different protein kinases regulates increase in the future. Frontiers in Molecular Neuroscience | www.frontiersin.org 5 November 2021 | Volume 14 | Article 786226 Català-Solsona et al. Nr4a2, Synaptic Plasticity and Memory A Total Presynaptic Postsynaptic C fraction fraction fraction Bi h Ba h Bi 2h Bi 2h 4h 4h Bi l Bi al Bi l sa sa 2 4 s kDa c c c c c c Ba Ba 75 50 Nr4a2 100 PSD95 37 Synaptophysin B Total Presynaptic Postsynaptic fraction fraction fraction 1 1 1 2 2 2 ip ip ip kDa ip ip ip H H H H H H 75 Nr4a2 50 100 PSD95 37 Synaptophysin FIGURE 2 | Nr4a2 transcription factor is present at the postsynaptic density both in mature hippocampal-cultured neurons and the adult mouse hippocampus. (A) Synaptoneurosomes from mature hippocampal-cultured neurons after bicuculline (bic; 50 µM) treatment. (B) Synaptoneurosomes of adult mouse hippocampus (hip). All figures correspond to representative images from Western blotting analysis. n ≥ 3. (C) Schematic model of Nr4a2 mobilization to nucleus and postsynaptic density fractions after neuronal activity. Nr4a2 contains a bipartite nuclear localization signal (NLS) only in the postmortem brain tissue, but also in the peripheral within its DBD and three leucine-rich nuclear export signals blood of PD patients (Le et al., 2008; Montarolo et al., 2016). (NES) in its LBD. Together, these signals regulate Nr4a2 Moreover, Nr4a2 mutations or polymorphisms were detected in shuttling in and out of the nucleus (García-Yagüe et al., 2013). sporadic and familial forms of PD (Xu et al., 2002; Le et al., Notably, data from our laboratory support the presence of Nr4a2 2003; Zheng et al., 2003; Grimes et al., 2006; Sleiman et al., in the postsynaptic density fraction of mature hippocampal 2009). Besides PD, evidence supports a role for Nr4a2 in the neuronal cultures treated with the GABA-A receptor antagonist pathogenesis of different CNS disorders (Figure 3). In recent bicuculline (Figure 2A). Moreover, Nr4a2 was also detected in years, much attention has been directed to Nr4a2 function the postsynaptic density fraction of synaptoneurosomes obtained in hippocampal synaptic plasticity, learning, and memory, from adult mouse hippocampus (Figure 2B). These data open the addressing much interest to the role of Nr4a2 in brain pathologies possibility that Nr4a2 could also be considered as a synaptically that course with cognitive or intellectual disabilities. One of the localized transcriptional regulator that will be transported, by an first brain diseases, besides PD, that was related to Nr4a2 was unknown mechanism, upon synaptic stimulation (Figure 2C). Alzheimer’s disease (AD). Further future work is needed to confirm the presence of Nr4a2 The potential of some nuclear receptors to serve as therapeutic in the synapse and the importance of this subcellular localization targets in disorders of cognition including AD has been reported in the already described role of Nr4a2 in hippocampal synaptic (Mandrekar-Colucci and Landreth, 2011; Skerrett et al., 2014). plasticity and memory formation. CREB is one of the transcription factors most extensively studied in AD, being disrupted by oligomeric forms of amyloid-β (oAβ) and leading to synaptic plasticity and memory deficits Nr4a2 IN COGNITIVE AND in AD (Vitolo et al., 2002; Saura and Valero, 2011). Moreover, NEUROPSYCHIATRIC BRAIN CREB transcription factor represents the crossroad of different DISORDERS synapse-to-nucleus pathways associated with changes in gene expression that underlie memory decline in AD (Marcello Parkinson’s disease (PD), which results from the degeneration of et al., 2018). Pioneer genome-wide transcriptome profile analyses midbrain dopaminergic neurons, was the first brain pathology of AD transgenic mice hippocampus revealed deregulation that was related to Nr4a2. Early reports showed that Nr4a2 of a transcriptional program dependent on CREB/CRTC1. expression was diminished in both aged and PD brains (Chu Specifically, APPSw,Ind mice at 6 months of age showed down- et al., 2002). Later, Nr4a2 gene expression was found reduced not regulation of diverse genes compared with wild type mice after Frontiers in Molecular Neuroscience | www.frontiersin.org 6 November 2021 | Volume 14 | Article 786226 Català-Solsona et al. Nr4a2, Synaptic Plasticity and Memory FIGURE 3 | Nr4a2 involvement in different cognitive and neuropsychiatric brain disorders. Schematic representation of Nr4a2 functions and/or alterations in neurodegenerative disorders (Parkinson’s disease, Alzheimer’s disease), schizophrenia and autism spectrum disorder. spatial training. These genes include Nr4a2 (España et al., It is noteworthy to mention that the functional roles of Nr4a2 2010; Parra-Damas et al., 2014). Indeed, a specific decrease of in AD could not be limited to its implication in synaptic function, Nr4a2 levels in Alzheimer’s pathology has been observed. Nr4a2 but also be extended to its involvement in the inflammatory mRNA levels were found diminished in Aβ1−42 -treated neuronal and neuronal death processes associated to AD. For example, it cells (Terzioglu-Usak et al., 2017) and in AD mouse models. was described that inflammatory stimulus up-regulated Nr4a2 A reduction in Nr4a2 mRNA was also seen in APPSw,Ind mice expression in microglia (Fan et al., 2009). This up-regulation when initial hippocampal-dependent spatial memory deficits could trigger a compensatory response through modulation appeared (España et al., 2010; Parra-Damas et al., 2014). of the NFκB action. Nr4a2 binds to target inflammatory A similar decrease was also reported in postmortem brains of gene promoters thought association with NFκB and the human AD patients, specifically in the frontal cortex, and the CoREST repressor complex down-regulating the expression of hippocampal formation (Parra-Damas et al., 2014; Moon et al., several pro-inflammatory genes in microglia and astrocytes 2019). A role of Nr4a2 in AD pathology was further supported by (Saijo et al., 2009). Furthermore, Nr4a2 neuroprotective effects the observation that Nr4a2 protein was prominently expressed are not limited to dopaminergic neurons. In glutamatergic in brain areas with Aβ accumulation in the 5XFAD mouse neurons, Nr4a2 also mediates CREB-induced neuroprotection model of AD and, notably, it was highly co-expressed with in response to stress by increasing BDNF levels in cerebellar Aβ at mice ages mimicking early stages of the disease (Oakley granule cells (Barneda-Zahonero et al., 2012) or up-regulating an et al., 2006). In addition, the number of Nr4a2-expressing cells anti-apoptotic gene program in hippocampal neurons (Volakakis significantly declined in the 5XFAD mouse in an age-dependent et al., 2010). Altogether, this anti-inflammatory and pro-survival manner, accompanied by increased plaque deposition, suggesting role in brain cells could also be involved in the reduction of a possible causal-effect relation between Nr4a2 levels and AD neuroinflammation and neuronal death seen in AD mice models progression (Moon et al., 2015). Moreover, in a recent study (Moon et al., 2019). performed by the same laboratory (Moon et al., 2019), they found Some reports have also associated Nr4a2 with schizophrenia. that knockdown of Nr4a2 significantly aggravated AD pathology This psychiatric disease is believed to result from subtle while its overexpression alleviated it, including a decrease in Aβ disturbances during brain development that lead to improper accumulation and neurodegeneration. Similar observations were function of synaptic transmission and plasticity of several obtained in 5XFAD mice treated with Nr4a2 activators. neurotransmitter systems (Birnbaum and Weinberger, 2017). Frontiers in Molecular Neuroscience | www.frontiersin.org 7 November 2021 | Volume 14 | Article 786226 Català-Solsona et al. Nr4a2, Synaptic Plasticity and Memory A consistent neuropathological observation in postmortem have suggested that several synthetic small molecules could bind brains of schizophrenic patients is the reduction in the density Nr4a2 in canonical and non-canonical binding pockets (Kim of small dendritic spines (MacDonald et al., 2017), which are et al., 2015; de Vera et al., 2019). Moreover, recent studies more plastic than bigger spines and, therefore, they are related have shown that the Nr4a2-LBD could be highly dynamic (de to learning and memory processes (Matsuzaki et al., 2001; Vera et al., 2019) allowing the binding of putative endogenous Trachtenberg et al., 2002). Missense mutations in the third ligands such as docosahexaenoic acid, prostaglandin E1 and exon of Nr4a2 (Buervenich et al., 2000) or altered expression the dopamine metabolite 5,6-dihydroxyndole (de Vera et al., of Nr4a2 in postmortem prefrontal cortex were detected in 2016; Bruning et al., 2019; Rajan et al., 2020). At present, it schizophrenic patients (Guillozet-Bongaarts et al., 2014; Corley is still unknown the physiological importance of these putative et al., 2016). Moreover, schizophrenic patients homozygous endogenous ligands on Nr4a2-mediated role in the CNS. for variants of the Nr4a2 promoter showed impairments in The identification of synthetic small molecules that could short-term memory assessed by the Backward Digit Span task modulate Nr4a2 transcriptional activity opens the possibility (Ruiz-Sánchez et al., 2021). A putative relationship between to provide target-based therapies for brain diseases related to Nr4a2 and schizophrenia was further supported by studies Nr4a2. Among the panoply of Nr4a2 modulators identified with rodents. Nr4a2 heterozygous mice displayed a pleiad of so far (Table 2), of special interest are the antimalarial drugs symptoms and behaviors related to schizophrenia (Rojas et al., amodiaquine (AQ) and chloroquine (CQ), which increase the 2007; Vuillermot et al., 2011). These mice showed hyperactivity in transcriptional function of Nr4a2 interacting with its LBD novel environments and were deficient in the passive avoidance through direct physical binding. These drugs were identified learning task. Moreover, a depression-like profile was also noticed as Nr4a2 agonists after screening a chemical library composed in the forced-swimming test (Rojas et al., 2007). The behavioral by Food and Drug Administration (FDA)-approved drugs in profile of Nr4a2 heterozygous mice regarding schizophrenia- a cell-based luciferase assay system (Kim et al., 2015). NMR relevant phenotypes was further extended by Vuillermot et al. spectroscopy suggested the binding of both drugs to the Nr4a2- (2011). They reported that Nr4a2-deficient male mice show LBD. Accordingly, AQ and CQ were able to increase the sensorimotor gating deficits consistent with an alteration in the transcriptional activity of Nr4a2 in human neuroblastoma cell glutamatergic system. This deficit in sensorimotor gating has lines (Kim et al., 2015). In addition, in preclinical studies, been consistently reported in schizophrenia patients (Swerdlow these compounds meaningfully improved behavioral deficits in and Geyer, 1998; Braff et al., 2001). Altogether, these findings rat models of PD without any noticeable sign of dyskinesia- indicate that Nr4a2-deficient mice display some phenotypic like behavior (Kim et al., 2015). Autophagic-lysosomal blockade characteristics of schizophrenia-like dysfunction. was also reported as one of their functions (Qiao et al., The presence of Nr4a2 deletions in patients with autism 2013). Recently, AQ has also been found to enhance cognitive spectrum disorder has also related Nr4a2 with intellectual functions by increasing adult hippocampal neurogenesis (Kim disability. In some reports, the deletion affected Nr4a2 and GPD2 et al., 2016). Importantly, 5XFAD mouse model of AD treated genes and caused intellectual disability and language impairment with the Nr4a2 agonist AQ showed robust reduction in typical (Barge-Schaapveld et al., 2013; Leppa Virpi et al., 2016). However, AD features including deposition of Aβ plaques, neuronal loss, other studies reported an individual with mild intellectual microgliosis and impairment of adult hippocampal neurogenesis, disability and prominent speech and language impairment that leading to significant improvement of cognitive functions in presented a deletion encompassing only Nr4a2 (Reuter et al., the Y-maze, which is a behavioral paradigm widely accepted 2017; Lévy et al., 2018). These studies provide further evidence to evaluate spatial working memory. The same study also for Nr4a2 haploinsufficiency being associated with intellectual showed for the first time that AQ treatment significantly disability and autism spectrum disorder. inhibited γ-secretase activity and enhanced degradation of Aβ All these studies clearly show that the involvement of Nr4a2 via up-regulation of insulin-degrading enzyme, an Aβ-degrading in brain diseases expands beyond PD and point out this protease (Moon et al., 2019). transcription factor as a promising candidate for the development Mercaptopurine was the first Nr4a2 agonist to be identified of novel therapeutic approaches. Future work should provide (Ordentlich et al., 2003). However, although it has been reported solid grounds to determine the precise contribution of Nr4a2 to that produces anti-inflammatory responses in microglia by each brain disorder. attenuation of TNF-α production (Huang et al., 2016), it is not considered a specific Nr4a2 agonist (Wansa et al., 2003; Huang et al., 2016). Other bicyclic compounds described to enhance THERAPEUTIC POTENTIAL OF Nr4a2 Nr4a2 transcriptional activity as homodimer or heterodimer are MODULATION isoxazolopyridinone-based compounds developed by Novartis AG (Hintermann et al., 2007). Among them, isoxazolo- As discussed above, until recently, it was considered that pyridinone 7e (IP7e) has an excellent oral bioavailability and Nr4a family members were orphan nuclear receptors since a fast and extensive brain uptake and has been reported their LBD seemed to avoid the binding of ligands due to the to ameliorate neuroinflammation and neurodegeneration in tight packing of bulky hydrophobic side chain residues (Wang an experimental model of autoimmune encephalomyelitis et al., 2003). However, during the last decade, several nuclear (Montarolo et al., 2014). However, a recent study suggests magnetic resonance (NMR) studies of the isolated Nr4a2-LBD that IP7e affects general transcription via Nr4a2-independent Frontiers in Molecular Neuroscience | www.frontiersin.org 8 November 2021 | Volume 14 | Article 786226 Català-Solsona et al. Nr4a2, Synaptic Plasticity and Memory TABLE 2 | Features of synthetic and endogenous Nr4a2 agonists. Compound Target Model Outcomes References Endogenous ligands Docosahexaenoic Nr4a2-LBD HEK-293T, MN9D cells Enhanced Nr4a2 transcriptional activity de Vera et al., 2016 acid Prostaglandins Nr4a2-LBD SK-N-BE(2)C, MN9D and Enhanced Nr4a2 transcriptional activity, Rajan et al., 2020 (PGE1 and PGA1) N27-A cells neuroprotection, improved behavioral deficits in a PD mouse model 5,6- Nr4a2-LBD JEG3 cells Enhanced Nr4a2 transcriptional activity Bruning et al., 2019 Dihydroxyindole (DHI) Synthetic ligands Antimalarial drugs Chloroquine Putative LBD residues DA neurons, Increased expression of DA genes; anti-inflammatory Kim et al., 2015 Amodiaquine PC12 cells responses, neuroprotection 6-OHDA lesioned rats (PD Improved behavioral deficits model) A375 melanoma cells Autophagic-lysosomal blockade Qiao et al., 2013 C57BL/6 mice Enhanced adult hippocampal neurogenesis, improved Kim et al., 2016 cognition 5XFAD mice Inhibited Aβ-mediated pathology; improved cognitive Moon et al., 2019 (AD model) functions Bicyclic compounds 6-Mercaptopurine AF-1 domain CV-1 cells Activation of both Nr4a2 and Nr4a3 Ordentlich et al., 2003 Microglia Anti-inflammatory responses Huang et al., 2016 Isoxazolopyridone- Putative LBD residues OF1 mice Increased DA levels in the SN and striatum Hintermann et al., 2007 based compounds (PD model) Inhibited expression of NFκB (attenuated inflammation Montarolo et al., 2014 (IP7e) Multiple sclerosis models and neurodegeneration), improved rotarod SA00025 Unknown 6-OHDA lesioned rats (PD Increased expression of DA genes; anti-inflammatory Smith et al., 2015 model) response and neuroprotection DIM-C analogs Both N- and C-terminus BV-2 cells Suppressed NFκB-induced genes De Miranda et al., 2015 Nr4a2; direct binding not MPTP lesioned rats (PD Increased expression of DA genes; anti-inflammatory supported model) response and neuroprotection C57BL/6 mice Enhanced long-term spatial memory in young mice, Chatterjee et al., 2020 rescued memory deficits in aged mice C57BL/6 mice Enhanced hippocampal LTP and long-term contextual Bridi et al., 2017 fear memory mechanisms (Munoz-Tello et al., 2020) seeding doubts about its CONCLUDING REMARKS AND FUTURE role as a specific Nr4a2 agonist. Another bicyclic compound, RESEARCH SA00025, a 2-aryl-6-phenylimidazol[1,2-α]pyridine derivative produced by Sanofi Aventis, was reported to exhibit partial During the last decade, many reports have supported a major neuroprotective effect in PD mouse models (Smith et al., role for the Nr4a family of nuclear receptors in hippocampal 2015). Although ligand screening shows an EC50 on the low synaptic plasticity and memory processes. The role of Nr4a2, nanomolar range (Jang et al., 2021), no data have shown its direct a member of this family, has received special attention. Several binding to Nr4a2. data suggest that Nr4a2 activation is necessary for hippocampal Another group of small molecules that have been identified to LTP and hippocampal-mediated learning tasks. However, many specifically activate members of the Nr4a family of transcription questions remain unanswered. It is still unknown which are factors are the paraphenyl substituted diindolylmethane analogs the signaling pathways that link synaptic activity to Nr4a2 or C-DIM (Li et al., 2012). Some of the C-DIM compounds, induction. We don’t know yet how Nr4a2 activation is enhancing as C-DIM5 and C-DIM8, have a greater specificity for Nr4a1 hippocampal plasticity and learning. Which are the genes than for Nr4a2. By contrast, C-DIM12 has higher affinity for activated or repressed by Nr4a2? Does Nr4a2 act on excitatory Nr4a2 and it is able to exert a potent anti-inflammatory and and/or inhibitory synapses? Is Nr4a2 modulating the pre neuroprotective role in a mouse model of PD (De Miranda and/or postsynaptic function? Which impact has glial Nr4a2 et al., 2015). Moreover, it enhances long-term spatial memory in in synaptic plasticity? Work during the following years will young mice and rescues memory deficits in aged mice (Chatterjee confirm whether Nr4a2 is present at the synapse and could et al., 2020). In summary, the possibility that Nr4a2 could act as a synaptonuclear messenger and how its subcellular be drug-targeted with several small synthetic molecules opens compartmentalization is modulated. an attractive and promising future for developing therapeutic Future studies should improve our knowledge of the role of strategies that include Nr4a2 as a druggable target. Nr4a2 in the cognitive impairment associated to several brain Frontiers in Molecular Neuroscience | www.frontiersin.org 9 November 2021 | Volume 14 | Article 786226 Català-Solsona et al. Nr4a2, Synaptic Plasticity and Memory pathologies. More pre-clinical studies are needed to confirm now, recent studies suggest that endogenous ligands could the importance of Nr4a2 activation in the hippocampus to indeed bind to Nr4a2-LBD. Future confirmation of the existence overcome the learning and memory deficits observed in animal of such endogenous ligands will open an important scenario, models of AD. It is necessary to extend the studies on the role since additional mechanisms, besides protein levels, could of Nr4a2 in AD beyond the 5XFAD mouse model. Also, an regulate Nr4a2 activity. extended behavioral characterization of learning and memory in these animals is needed. It would be also relevant to know whether Nr4a2 activation has any impact on Aβ plaques and AUTHOR CONTRIBUTIONS neurofibrillary tangles, which are the neurohistological hallmarks of AD. Moreover, the relationship between Nr4a2 and some JC-S, AM-M, and JR-Á conceived the idea for this review psychiatric diseases has been already established. Thus, it would and reviewed the literature. JC-S wrote the first draft be also important to address the impact of Nr4a2 on behavioral of the manuscript and created the figures. JR-Á wrote and psychological symptoms with new studies in animals’ the final draft. JC-S and AM-M revised the manuscript. models for these diseases such as schizophrenia or autism All authors contributed to the article and approved the spectrum disorder. submitted version. All these studies will benefit from the already known Nr4a2 ligands that allow us to consider Nr4a2 as a druggable target. However, to provide future target-based therapeutic FUNDING interventions, more work should be done to modify existing chemical structures to increase the specificity of Nr4a2 agonists, This work was supported by the grants from Ministerio increase their blood-brain barrier permeability and improve their de Ciencia, Innovación y Universidades (SAF2017-89271-R pharmacokinetic characteristics. and PID2020-117510RB-I00), CIBERNED (CB06/05/0042) and Finally, another important question needs to be answered Generalitat de Catalunya (SGR2017-0749) to JR-Á. JC-S was during the next decade. Is Nr4a2 an orphan nuclear receptor? a recipient of a Fellowship from the Ministerio de Ciencia, Although this question has been considered affirmative until Innovación y Universidades (FPU-14/05392). REFERENCES Bensinger, S. J., and Tontonoz, P. (2009). A Nurr1 Pathway for Neuroprotection. Cell 137, 26–28. doi: 10.1016/j.cell.2009.03.024 Abraham, W. C., Jones, O. D., and Glanzman, D. L. (2019). Is plasticity of synapses Birnbaum, R., and Weinberger, D. R. (2017). Genetic insights into the the mechanism of long-term memory storage? NPJ Sci. Learn. 4:9. neurodevelopmental origins of schizophrenia. Nat. Rev. Neurosci. 18, 727–740. Ahn, J. H., Lee, J. S., Cho, J. H., Park, J. H., Lee, T. K., Song, M., et al. (2018). Age- doi: 10.1038/nrn.2017.125 dependent decrease of Nurr1 protein expression in the gerbil hippocampus. Bourtchuladze, R., Frenguelli, B., Blendy, J., Cioffi, D., Schutz, G., and Silva, A. J. Biomed. Rep. 8, 517–522. doi: 10.3892/br.2018.1094 (1994). Deficient long-term memory in mice with a targeted mutation of the Alberini, C. M. (2009). Transcription factors in long-term memory and cAMP-responsive element-binding protein. Cell 79, 59–68. doi: 10.1016/0092- synaptic plasticity. Physiol. Rev. 89, 121–145. doi: 10.1152/physrev.00017. 8674(94)90400-6 2008 Braff, D. L., Geyer, M. A., and Swerdlow, N. R. (2001). Human studies of prepulse Aldavert-Vera, L., Huguet, G., Costa-Miserachs, D., Ortiz, S. P. D., Kádár, E., inhibition of startle: normal subjects, patient groups, and pharmacological Morgado-Bernal, I., et al. (2013). Intracranial self-stimulation facilitates active- studies. Psychopharmacology 156, 234–258. doi: 10.1007/s00213010 avoidance retention and induces expression of c-Fos and Nurr1 in rat brain 0810 memory systems. Behav. Brain Res. 250, 46–57. doi: 10.1016/j.bbr.2013. Bridi, M. S., and Abel, T. (2013). The NR4A orphan nuclear receptors mediate 04.025 transcription-dependent hippocampal synaptic plasticity. Neurobiol. Learn. Altarejos, J. Y., and Montminy, M. (2011). CREB and the CRTC co-activators: Mem. 105, 151–158. doi: 10.1016/j.nlm.2013.06.020 sensors for hormonal and metabolic signals. Nat. Rev. Mol. Cell Biol. 12, Bridi, M. S., Hawk, J. D., Chatterjee, S., Safe, S., and Abel, T. (2017). 141–151. doi: 10.1038/nrm3072 Pharmacological activators of the NR4A nuclear receptors enhance LTP in a Barge-Schaapveld, D. Q. C. M., Ofman, R., Knegt, A. C., Alders, M., Höhne, W., CREB/CBP-dependent manner. Neuropsychopharmacology 42, 1243–1253. doi: Kemp, S., et al. (2013). Intellectual disability and hemizygous GPD2 mutation. 10.1038/npp.2016.253 Am. J. Med. Genet. Part A 161, 1044–1050. doi: 10.1002/ajmg.a.35873 Bruning, J. M., Wang, Y., Oltrabella, F., Tian, B., Kholodar, S. A., Liu, H., et al. Barneda-Zahonero, B., Servitja, J.-M., Badiola, N., Miñano-Molina, A. J., Fadó, (2019). Covalent modification and regulation of the nuclear receptor Nurr1 by R., Saura, C. A., et al. (2012). Nurr1 protein is required for N-Methyl-d- a dopamine metabolite. Cell Chem. Biol. 26, 674.e676–685.e676. doi: 10.1016/j. Aspartic Acid (n.d.) receptor-mediated neuronal survival. J. Biol. Chem. 287, chembiol.2019.02.002 11351–11362. doi: 10.1074/jbc.M111.272427 Buervenich, S., Carmine, A., Arvidsson, M., Xiang, F., Zhang, Z., Sydow, O., et al. Bartsch, D., Casadio, A., Karl, K. A., Serodio, P., and Kandel, E. R. (1998). CREB1 (2000). NURR1 Mutations in cases of schizophrenia and manic-depressive encodes a nuclear activator, a repressor, and a cytoplasmic modulator that disorder. Am. J. Med. Genet. 96, 808–813. doi: 10.1002/1096-8628(20001204) form a regulatory unit critical for long-term facilitation. Cell 95, 211–223. 96:6<808::aid-ajmg23>3.0.co;2-e doi: 10.1016/s0092-8674(00)81752-3 Chatterjee, S., Walsh, E. N., Yan, A. L., Giese, K. P., Safe, S., and Abel, T. Bekinschtein, P., Cammarota, M., and Medina, J. H. (2014). BDNF and memory (2020). Pharmacological activation of Nr4a rescues age-associated memory processing. Neuropharmacology 76, 677–683. doi: 10.1016/j.neuropharm.2013. decline. Neurobiol. Aging 85, 140–144. doi: 10.1016/j.neurobiolaging.2019. 04.024 10.001 Benito, E., and Barco, A. (2015). The neuronal activity-driven transcriptome. Mol. Chen, X.-X., Qian, Y., Wang, X.-P., Tang, Z.-W., Xu, J.-T., Lin, H., et al. Neurobiol. 51, 1071–1088. (2018). Nurr1 promotes neurogenesis of dopaminergic neuron and represses Frontiers in Molecular Neuroscience | www.frontiersin.org 10 November 2021 | Volume 14 | Article 786226 Català-Solsona et al. Nr4a2, Synaptic Plasticity and Memory inflammatory factors in the transwell coculture system of neural stem cells and Hammond, S. L., Safe, S., and Tjalkens, R. B. (2015). A novel synthetic activator microglia. CNS Neurosci. Therapeutics 24, 790–800. doi: 10.1111/cns.12825 of Nurr1 induces dopaminergic gene expression and protects against 6- Ch’ng, T. H., and Martin, K. C. (2011). Synapse-to-nucleus signaling. Curr. Opin. hydroxydopamine neurotoxicity in vitro. Neurosci. Lett. 607, 83–89. doi: 10. Neurobiol. 21, 345–352. 1016/j.neulet.2015.09.015 Ch’ng Toh, H., Uzgil, B., Lin, P., Avliyakulov Nuraly, K., O’Dell Thomas, J., and Hawk, J. D., and Abel, T. (2011). The role of NR4A transcription factors in memory Martin Kelsey, C. (2012). Activity-dependent transport of the transcriptional formation. Brain Res. Bull. 85, 21–29. doi: 10.1016/j.brainresbull.2011.02.001 coactivator CRTC1 from synapse to nucleus. Cell 150, 207–221. Hawk, J. D., Bookout, A. L., Poplawski, S. G., Bridi, M., Rao, A. J., Sulewski, M. E., Chu, Y., Kompoliti, K., Cochran, E. J., Mufson, E. J., and Kordower, J. H. (2002). et al. (2012). NR4A nuclear receptors support memory enhancement by histone Age-related decreases in Nurr1 immunoreactivity in the human substantia deacetylase inhibitors. J. Clin. Investigat. 122, 3593–3602. nigra. J. Comparat. Neurol. 450, 203–214. doi: 10.1002/cne.10261 Heo, S., Diering, G. H., Na, C. H., Nirujogi, R. S., Bachman, J. L., Pandey, A., et al. Chuang, H.-C., Huang, T.-N., and Hsueh, Y.-P. (2015). T-Brain-1 – A potential (2018). Identification of long-lived synaptic proteins by proteomic analysis of master regulator in autism spectrum disorders. Autism Res. 8, 412–426. doi: synaptosome protein turnover. Proc. Natl. Acad. Sci. U.S.A. 115:E3827. doi: 10.1002/aur.1456 10.1073/pnas.1720956115 Colón-Cesario, W. I., Martínez-Montemayor, M. M., Morales, S., Félix, J., Cruz, Hintermann, S., Chiesi, M., von Krosigk, U., Mathé, D., Felber, R., and Hengerer, J., Adorno, M., et al. (2006). Knockdown of Nurr1 in the rat hippocampus: B. (2007). Identification of a series of highly potent activators of the Nurr1 Implications to spatial discrimination learning and memory. Learn. Mem. 13, signaling pathway. Bioorganic Med. Chem. Lett. 17, 193–196. doi: 10.1016/j. 734–744. doi: 10.1101/lm.407706 bmcl.2006.09.062 Corley, S. M., Tsai, S.-Y., Wilkins, M. R., and Shannon Weickert, C. (2016). Huang, H.-Y., Chang, H.-F., Tsai, M.-J., Chen, J.-S., and Wang, M.-J. (2016). 6- Transcriptomic analysis shows decreased cortical expression of NR4A1, NR4A2 Mercaptopurine attenuates tumor necrosis factor-α production in microglia and RXRB in schizophrenia and provides evidence for nuclear receptor through Nur77-mediated transrepression and PI3K/Akt/mTOR signaling- dysregulation. PLoS One 11:e0166944. doi: 10.1371/journal.pone.0166944 mediated translational regulation. J. Neuroinflamm. 13:78. doi: 10.1186/ Darcy, M. J., Calvin, K., Cavnar, K., and Ouimet, C. C. (2010). Regional and s12974-016-0543-5 subcellular distribution of HDAC4 in mouse brain. J. Comparat. Neurol. 518, Ichinose, H., Ohye, T., Suzuki, T., Sumi-Ichinose, C., Nomura, T., Hagino, Y., 722–740. doi: 10.1002/cne.22241 et al. (1999). Molecular cloning of the human Nurr1 gene: characterization of De Miranda, B. R., Popichak, K. A., Hammond, S. L., Jorgensen, B. A., the human gene and cDNAs. Gene 230, 233–239. doi: 10.1016/s0378-1119(99) Phillips, A. T., Safe, S., et al. (2015). The Nurr1 activator 1,1-Bis(30 -Indolyl)- 00065-7 1-(p-Chlorophenyl)methane blocks inflammatory gene expression in BV-2 Jang, Y., Kim, W., Leblanc, P., Kim, C.-H., and Kim, K.-S. (2021). Potent synthetic microglial cells by inhibiting nuclear factor κB. Mol. Pharmacol. 87, 1021–1034. and endogenous ligands for the adopted orphan nuclear receptor Nurr1. Exp. doi: 10.1124/mol.114.095398 Mol. Med. 53, 19–29. doi: 10.1038/s12276-021-00555-5 de Vera, I. M. S., Giri, P. K., Munoz-Tello, P., Brust, R., Fuhrmann, J., Matta- Jeon, S. G., Yoo, A., Chun, D. W., Hong, S. B., Chung, H., Kim, J.-I., et al. (2020). Camacho, E., et al. (2016). Identification of a binding site for unsaturated fatty The critical role of Nurr1 as a mediator and therapeutic target in Alzheimer’s acids in the orphan nuclear receptor Nurr1. ACS Chem. Biol. 11, 1795–1799. disease-related pathogenesis. Aging Dis. 11, 705–724. doi: 10.14336/AD.2019. doi: 10.1021/acschembio.6b00037 0718 de Vera, I. M. S., Munoz-Tello, P., Zheng, J., Dharmarajan, V., Marciano, Jiang, L., Dai, S., Li, J., Liang, X., Qu, L., Chen, X., et al (2019). Structural basis D. P., Matta-Camacho, E., et al. (2019). Defining a canonical ligand- of binding of homodimers of the nuclear receptor NR4A2 to selective Nur- binding pocket in the orphan nuclear receptor Nurr1. Structure 27, responsive DNA elements. J. Biol. Chem. 294, 19795–19803. doi: 10.1074/jbc. 66.e65–77.e65. RA119.010730 Decressac, M., Volakakis, N., Björklund, A., and Perlmann, T. (2013). NURR1 Jo, A. Y., Kim, M.-Y., Lee, H.-S., Rhee, Y.-H., Lee, J.-E., Baek, K.-H., et al. in Parkinson disease—from pathogenesis to therapeutic potential. Nat. Rev. (2009). Generation of dopamine neurons with improved cell survival and Neurol. 9, 629–636. doi: 10.1038/nrneurol.2013.209 phenotype maintenance using a degradation-resistant Nurr1 mutant. Stem Cells Dunah, A. W., Hueske, E., Wyszynski, M., Hoogenraad, C. C., Jaworski, J., 27, 2238–2246. doi: 10.1002/stem.146 Pak, D. T., et al. (2005). LAR receptor protein tyrosine phosphatases in Kadkhodaei, B., Ito, T., Joodmardi, E., Mattsson, B., Rouillard, C., Carta, M., et al. the development and maintenance of excitatory synapses. Nat. Neurosci. 8, (2009). Nurr1 is required for maintenance of maturing and adult midbrain 458–467. doi: 10.1038/nn1416 dopamine neurons. J. Neurosci. 29:15923. España, J., Valero, J., Miñano-Molina, A. J., Masgrau, R., Martín, E., Guardia- Kaldun, J. C., and Sprecher, S. G. (2019). Initiated by CREB: resolving gene Laguarta, C., et al. (2010). β-Amyloid disrupts activity-dependent gene regulatory programs in learning and memory. BioEssays 41:1900045. doi: 10. transcription required for memory through the CREB coactivator CRTC1. 1002/bies.201900045 J. Neurosci. 30, 9402–9410. doi: 10.1523/JNEUROSCI.2154-10.2010 Kaltschmidt, C., Kaltschmidt, B., and Baeuerle, P. A. (1993). Brain synapses contain Fan, X., Luo, G., Ming, M., Pu, P., Li, L., Yang, D., et al. (2009). Nurr1 expression inducible forms of the transcription factor NF-κB. Mechan. Dev. 43, 135–147. and its modulation in Microglia. Neuroimmunomodulation 16, 162–170. doi: doi: 10.1016/0925-4773(93)90031-r 10.1159/000204229 Keeley, M. B., Wood, M. A., Isiegas, C., Stein, J., Hellman, K., Hannenhalli, S., et al. Fleischmann, A., Hvalby, O., Jensen, V., Strekalova, T., Zacher, C., Layer, L. E., (2006). Differential transcriptional response to nonassociative and associative et al. (2003). Impaired long-term memory and NR2A-Type NMDA receptor- components of classical fear conditioning in the amygdala and hippocampus. dependent synaptic plasticity in mice lacking c-fos in the CNS. J. Neurosci. Learn. Mem. 13, 135–142. doi: 10.1101/lm.86906 23:9116. doi: 10.1523/JNEUROSCI.23-27-09116.2003 Kim, C.-H., Han, B.-S., Moon, J., Kim, D.-J., Shin, J., Rajan, S., et al. (2015). Nuclear García-Yagüe, Á. J., Rada, P., Rojo, A. I., Lastres-Becker, I., and Cuadrado, A. receptor Nurr1 agonists enhance its dual functions and improve behavioral (2013). Nuclear import and export signals control the subcellular localization deficits in an animal model of Parkinson’s disease. Proc. Natl. Acad. Sci. U.S.A. of Nurr1 protein in response to oxidative stress. J. Biol. Chem. 288, 5506–5517. 112, 8756–8761. doi: 10.1073/pnas.1509742112 doi: 10.1074/jbc.M112.439190 Kim, J.-I., Jeon, S. G., Kim, K. A., Kim, Y. J., Song, E. J., Choi, J., et al. (2016). Grimes, D. A., Han, F., Panisset, M., Racacho, L., Xiao, F., Zou, R., et al. (2006). The pharmacological stimulation of Nurr1 improves cognitive functions via Translated mutation in the Nurr1 gene as a cause for Parkinson’s disease. Mov. enhancement of adult hippocampal neurogenesis. Stem Cell Res. 17, 534–543. Disord. 21, 906–909. doi: 10.1016/j.scr.2016.09.027 Guillozet-Bongaarts, A. L., Hyde, T. M., Dalley, R. A., Hawrylycz, M. J., Henry, A., Kim, S. M., Cho, S. Y., Kim, M. W., Roh, S. R., Shin, H. S., Suh, Y. H., et al. Hof, P. R., et al. (2014). Altered gene expression in the dorsolateral prefrontal (2020). Genome-Wide analysis identifies NURR1-controlled network of new cortex of individuals with schizophrenia. Mol. Psychiatry 19, 478–485. doi: synapse formation and cell cycle arrest in human neural stem cells. Mol. Cells 10.1038/mp.2013.30 43, 551–571. doi: 10.14348/molcells.2020.0071 Hagenston, A. M., and Bading, H. (2011). Calcium signaling in synapse-to-nucleus Klann, E., and Dever, T. E. (2004). Biochemical mechanisms for translational communication. Cold Spring Harb. Perspect. Biol. 3:a004564. regulation in synaptic plasticity. Nat. Rev. Neurosci. 5, 931–942. Frontiers in Molecular Neuroscience | www.frontiersin.org 11 November 2021 | Volume 14 | Article 786226 Català-Solsona et al. Nr4a2, Synaptic Plasticity and Memory Kovács, K. A., Steullet, P., Steinmann, M., Do, K. Q., Magistretti, P. J., Halfon, O., Montarolo, F., Perga, S., Martire, S., Navone, D. N., Marchet, A., Leotta, D., et al. et al. (2007). TORC1 is a calcium- and cAMP-sensitive coincidence detector (2016). Altered NR4A subfamily gene expression level in peripheral blood of involved in hippocampal long-term synaptic plasticity. Proc. Natl. Acad. Sci. Parkinson’s and Alzheimer’s disease patients. Neurotoxicity Res. 30, 338–344. U.S.A. 104:4700. doi: 10.1073/pnas.0607524104 doi: 10.1007/s12640-016-9626-4 Kwapis, J. L., Alaghband, Y., López, A. J., Long, J. M., Li, X., Shu, G., et al. Montarolo, F., Raffaele, C., Perga, S., Martire, S., Finardi, A., Furlan, R., et al. (2014). (2019). HDAC3-mediated repression of the &It;em>Nr4a&It;/em> family Effects of isoxazolo-pyridinone 7e, a potent activator of the Nurr1 signaling contributes to age-related impairments in long-term memory. J. Neurosci. pathway, on experimental autoimmune encephalomyelitis in mice. PLoS One 39:4999. 9:e108791. doi: 10.1371/journal.pone.0108791 Lai, K.-O., Zhao, Y., Ch’ng, T. H., and Martin, K. C. (2008). Importin-mediated Moon, M., Jeong, I., Kim, C.-H., Kim, J., Lee, P. K. J., Mook-Jung, I., et al. retrograde transport of CREB2 from distal processes to the nucleus in neurons. (2015). Correlation between orphan nuclear receptor Nurr1 expression and Proc. Natl. Acad. Sci. U.S.A. 105:17175. doi: 10.1073/pnas.0803906105 amyloid deposition in 5XFAD mice, an animal model of Alzheimer’s disease. Le, W., Pan, T., Huang, M., Xu, P., Xie, W., Zhu, W., et al. (2008). Decreased J. Neurochem. 132, 254–262. doi: 10.1111/jnc.12935 NURR1 gene expression in patients with Parkinson’s disease. J. Neurol. Sci. 273, Moon, M., Jung, E. S., Jeon, S. G., Cha, M.-Y., Jang, Y., Kim, W., et al. (2019). Nurr1 29–33. (NR4A2) regulates Alzheimer’s disease-related pathogenesis and cognitive Le, W.-D., Conneely, O. M., Zou, L., He, Y., Saucedo-Cardenas, O., Jankovic, function in the 5XFAD mouse model. Aging Cell 18:e12866. doi: 10.1111/acel. J., et al. (1999). Selective agenesis of mesencephalic dopaminergic neurons in 12866 Nurr1-Deficient mice. Exp. Neurol. 159, 451–458. doi: 10.1006/exnr.1999.7191 Munoz-Tello, P., Lin, H., Khan, P., de Vera, I. M. S., Kamenecka, T. M., and Le, W.-D., Xu, P., Jankovic, J., Jiang, H., Appel, S. H., Smith, R. G., et al. (2003). Kojetin, D. J. (2020). Assessment of NR4A ligands that directly bind and Mutations in NR4A2 associated with familial Parkinson disease. Nat. Genet. 33, modulate the orphan nuclear receptor Nurr1. J. Med. Chem. 63, 15639–15654. 85–89. doi: 10.1021/acs.jmedchem.0c00894 Leppa Virpi, M., Kravitz Stephanie, N., Martin Christa, L., Andrieux, J., Le Caignec, Nonaka, M., Kim, R., Fukushima, H., Sasaki, K., Suzuki, K., Okamura, M., et al. C., Martin-Coignard, D., et al. (2016). Rare inherited and de novo CNVs reveal (2014). Region-Specific activation of CRTC1-CREB signaling mediates long- complex contributions to ASD risk in multiplex families. Am. J. Hum. Genet. term fear memory. Neuron 84, 92–106. doi: 10.1016/j.neuron.2014.08.049 99, 540–554. doi: 10.1016/j.ajhg.2016.06.036 Oakley, H., Cole, S. L., Logan, S., Maus, E., Shao, P., Craft, J., et al. (2006). Lévy, J., Grotto, S., Mignot, C., Maruani, A., Delahaye-Duriez, A., Benzacken, B., Intraneuronal β-Amyloid aggregates, neurodegeneration, and neuron loss et al. (2018). NR4A2 haploinsufficiency is associated with intellectual disability in transgenic mice with five familial Alzheimer's disease mutations: and autism spectrum disorder. Clin. Genet. 94, 264–268. doi: 10.1111/cge.13383 potential factors in amyloid plaque formation. J. Neurosci. 26:10129. doi: 10. Li, X., Lee, S.-O., and Safe, S. (2012). Structure-dependent activation of 1523/JNEUROSCI.1202-06.2006 NR4A2 (Nurr1) by 1,1-bis(30 -indolyl)-1-(aromatic)methane analogs Oliveira, A., Martinho, R., Serrão, P., and Moreira-Rodrigues, M. (2018). in pancreatic cancer cells. Biochem. Pharmacol. 83, 1445–1455. doi: Epinephrine released during traumatic events may strengthen contextual 10.1016/j.bcp.2012.02.021 fear memory through increased hippocampus mRNA expression of Nr4a MacDonald, M. L., Alhassan, J., Newman, J. T., Richard, M., Gu, H., Kelly, R. M., transcription factors. Front. Mol. Neurosci. 11:334. doi: 10.3389/fnmol.2018. et al. (2017). Selective loss of smaller spines in schizophrenia. Am. J. Psychiatry 00334 174, 586–594. doi: 10.1176/appi.ajp.2017.16070814 Ordentlich, P., Yan, Y., Zhou, S., and Heyman, R. A. (2003). Identification of the Mandrekar-Colucci, S., and Landreth, G. E. (2011). Nuclear receptors as antineoplastic agent 6-Mercaptopurine as an activator of the orphan nuclear therapeutic targets for Alzheimer’s disease. Expert Opin. Therapeutic Targets 15, hormone receptor Nurr1∗ . J. Biol. Chem. 278, 24791–24799. doi: 10.1074/jbc. 1085–1097. doi: 10.1517/14728222.2011.594043 M302167200 Marcello, E., Di Luca, M., and Gardoni, F. (2018). Synapse-to-nucleus Parra-Damas, A., Chen, M., Enriquez-Barreto, L., Ortega, L., Acosta, S., Perna, communication: from developmental disorders to Alzheimer’s disease. Curr. J. C., et al. (2017a). CRTC1 function during memory encoding is disrupted in Opin. Neurobiol. 48, 160–166. doi: 10.1016/j.conb.2017.12.017 neurodegeneration. Biol. Psychiatry 81, 111–123. doi: 10.1016/j.biopsych.2016. Martin, S. J., Grimwood, P. D., and Morris, R. G. M. (2000). Synaptic plasticity and 06.025 memory: an evaluation of the hypothesis. Annu. Rev. Neurosci. 23, 649–711. Parra-Damas, A., Rubió-Ferrarons, L., Shen, J., and Saura, C. A. (2017b). CRTC1 Matsuzaki, M., Ellis-Davies, G. C. R., Nemoto, T., Miyashita, Y., Iino, M., and Kasai, mediates preferential transcription at neuronal activity-regulated CRE/TATA H. (2001). Dendritic spine geometry is critical for AMPA receptor expression promoters. Sci. Rep. 7:18004. doi: 10.1038/s41598-017-18215-y in hippocampal CA1 pyramidal neurons. Nat. Neurosci. 4, 1086–1092. doi: Parra-Damas, A., Valero, J., Chen, M., España, J., Martín, E., Ferrer, I., 10.1038/nn736 et al. (2014). Crtc1 activates a transcriptional program deregulated at early Maxwell, M. A., and Muscat, G. E. (2006). The NR4A subgroup: immediate early Alzheimer's disease-related stages. J. Neurosci. 34:5776. doi: 10.1523/ response genes with pleiotropic physiological roles. Nucl. Recept. Signal. 4:e002. JNEUROSCI.5288-13.2014 doi: 10.1621/nrs.04002 Pegoraro, S., Broccard, F. D., Ruaro, M. E., Bianchini, D., Avossa, D., Pastore, McNamara, R. K., Hussain, R. J., Simon, E. J., Stumpo, D. J., Blackshear, G., et al. (2010). Sequential steps underlying neuronal plasticity induced by a P. J., Abel, T., et al. (2005). Effect of myristoylated alanine-rich C kinase transient exposure to gabazine. J. Cell. Physiol. 222, 713–728. doi: 10.1002/jcp. substrate (MARCKS) overexpression on hippocampus-dependent learning and 21998 hippocampal synaptic plasticity in MARCKS transgenic mice. Hippocampus 15, Peña de Ortiz, S., Maldonado-Vlaar, C. S., and Carrasquillo, Y. (2000). 675–683. doi: 10.1002/hipo.20089 Hippocampal expression of the orphan nuclear receptor gene hzf-3/nurr1 McNulty, S. E., Barrett, R. M., Vogel-Ciernia, A., Malvaez, M., Hernandez, N., during spatial discrimination learning. Neurobiol. Learn. Mem. 74, 161–178. Davatolhagh, M. F., et al. (2012). Differential roles for Nr4a1 and Nr4a2 in doi: 10.1006/nlme.1999.3952 object location vs. object recognition long-term memory. Learn. Mem. 19, Qiao, S., Tao, S., Rojo de la Vega, M., Park, S. L., Vonderfecht, A. A., Jacobs, S. L., 588–592. doi: 10.1101/lm.026385.112 et al. (2013). The antimalarial amodiaquine causes autophagic-lysosomal and McQuown, S. C., Barrett, R. M., Matheos, D. P., Post, R. J., Rogge, G. A., Alenghat, proliferative blockade sensitizing human melanoma cells to starvation- and T., et al. (2011). HDAC3 is a critical negative regulator of long-term memory chemotherapy-induced cell death. Autophagy 9, 2087–2102. doi: 10.4161/auto. formation. J. Neurosci. 31:764. 26506 Meffert, M. K., Chang, J. M., Wiltgen, B. J., Fanselow, M. S., and Baltimore, D. Quina, L. A., Wang, S., Ng, L., and Turner, E. E. (2009). Brn3a and Nurr1 mediate (2003). NF-κB functions in synaptic signaling and behavior. Nat. Neurosci. 6, a gene regulatory pathway for habenula development. J. Neurosci. 29:14309. 1072–1078. doi: 10.1038/nn1110 doi: 10.1523/JNEUROSCI.2430-09.2009 Miranda, M., Morici, J. F., Zanoni, M. B., and Bekinschtein, P. (2019). Brain- Rajan, S., Jang, Y., Kim, C. H., Kim, W., Toh, H. T., Jeon, J., et al. (2020). PGE1 and derived neurotrophic factor: a key molecule for memory in the healthy and the PGA1 bind to Nurr1 and activate its transcriptional function. Nat. Chem. Biol. pathological brain. Front. Cell. Neurosci. 13:363. doi: 10.3389/fncel.2019.00363 16, 876–886. doi: 10.1038/s41589-020-0553-6 Frontiers in Molecular Neuroscience | www.frontiersin.org 12 November 2021 | Volume 14 | Article 786226 Català-Solsona et al. Nr4a2, Synaptic Plasticity and Memory Ranhotra, H. S. (2015). The NR4A orphan nuclear receptors: mediators in plasticity via CREB: CBP-dependent transcriptional activation. J. Neurosci. metabolism and diseases. J. Receptors Signal Transduct. 35, 184–188. doi: 10. 27:6128. doi: 10.1523/JNEUROSCI.0296-07.2007 3109/10799893.2014.948555 Vitolo, O. V., Sant’Angelo, A., Costanzo, V., Battaglia, F., Arancio, O., and Reuter, M. S., Krumbiegel, M., Schlüter, G., Ekici, A. B., Reis, A., and Zweier, C. Shelanski, M. (2002). Amyloid β-peptide inhibition of the PKA/CREB pathway (2017). Haploinsufficiency of NR4A2 is associated with a neurodevelopmental and long-term potentiation: reversibility by drugs that enhance cAMP phenotype with prominent language impairment. Am. J. Med. Genet. Part A signaling. Proc. Natl. Acad. Sci. U.S.A. 99, 13217–13221. doi: 10.1073/pnas. 173, 2231–2234. doi: 10.1002/ajmg.a.38288 172504199 Rojas, P., Joodmardi, E., Hong, Y., Perlmann, T., and Ögren, S. O. (2007). Adult Volakakis, N., Kadkhodaei, B., Joodmardi, E., Wallis, K., Panman, L., Silvaggi, J., mice with reduced Nurr1 expression: an animal model for schizophrenia. Mol. et al. (2010). NR4A orphan nuclear receptors as mediators of CREB-dependent Psychiatry 12, 756–766. doi: 10.1038/sj.mp.4001993 neuroprotection. Proc. Natl. Acad. Sci. U.S.A. 107:12317. doi: 10.1073/pnas. Ruiz-Sánchez, E., Jiménez-Genchi, J., Alcántara-Flores, Y. M., Castañeda- 1007088107 González, C. J., Aviña-Cervantes, C. L., Yescas, P., et al. (2021). Working Volpicelli, F., Caiazzo, M., Greco, D., Consales, C., Leone, L., Perrone-Capano, C., memory deficits in schizophrenia are associated with the rs34884856 variant et al. (2007). Bdnf gene is a downstream target of Nurr1 transcription factor in and expression levels of the NR4A2 gene in a sample Mexican population: a rat midbrain neurons in vitro. J. Neurochem. 102, 441–453. doi: 10.1111/j.1471- case control study. BMC Psychiatry 21:86. doi: 10.1186/s12888-021-03081-w 4159.2007.04494.x Safe, S., Jin, U.-H., Morpurgo, B., Abudayyeh, A., Singh, M., and Tjalkens, R. B. von Hertzen, L. S. J., and Giese, K. P. (2005). Memory reconsolidation engages only (2016). Nuclear receptor 4A (NR4A) family – orphans no more. J. Steroid a subset of immediate-early genes induced during consolidation. J. Neurosci. Biochem. Mol. Biol. 157, 48–60. doi: 10.1016/j.jsbmb.2015.04.016 25:1935. doi: 10.1523/JNEUROSCI.4707-04.2005 Saijo, K., Winner, B., Carson, C. T., Collier, J. G., Boyer, L., Rosenfeld, M. G., Vuillermot, S., Joodmardi, E., Perlmann, T., Ove Ögren, S., Feldon, J., and Meyer, et al. (2009). A Nurr1/CoREST pathway in microglia and astrocytes protects U. (2011). Schizophrenia-relevant behaviors in a genetic mouse model of dopaminergic neurons from inflammation-induced death. Cell 137, 47–59. doi: constitutive Nurr1 deficiency. Genes Brain Behav. 10, 589–603. doi: 10.1111/ 10.1016/j.cell.2009.01.038 j.1601-183X.2011.00698.x Saucedo-Cardenas, O., and Conneely, O. M. (1996). Comparative distribution of Wang, Z., Benoit, G., Liu, J., Prasad, S., Aarnisalo, P., Liu, X., et al. (2003). Structure NURR1 and NUR77 nuclear receptors in the mouse central nervous system. and function of Nurr1 identifies a class of ligand-independent nuclear receptors. J. Mol. Neurosci. 7, 51–63. doi: 10.1007/BF02736848 Nature 423, 555–560. Saucedo-Cardenas, O., Quintana-Hau, J. D., Le, W.-D., Smidt, M. P., Cox, Wansa, K., Harris, J., Yan, G., Ordentlich, P., and Muscat, G. (2003). The J. J., De Mayo, F., et al. (1998). Nurr1 is essential for the induction of AF-1 Domain of the orphan nuclear receptor NOR-1 mediates trans- the dopaminergic phenotype and the survival of ventral mesencephalic late activation, coactivator recruitment, and activation by the purine anti-metabolite dopaminergic precursor neurons. Proc. Natl. Acad. Sci. U.S.A. 95, 4013–4018. 6-Mercaptopurine. J. Biol. Chem. 278, 24776–24790. doi: 10.1074/jbc. doi: 10.1073/pnas.95.7.4013 M300088200 Saura, C. A., and Valero, J. (2011). The role of CREB signaling in Xu, P. Y., Liang, R., Jankovic, J., Hunter, C., Zeng, Y. X., Ashizawa, T., et al. (2002). Alzheimer’s disease and other cognitive disorders. Rev. Neurosci. 22, Association of homozygous 7048G7049 variant in the intron six of Nurr1 gene 153–169. with Parkinson’s disease. Neurology 58:881. doi: 10.1212/wnl.58.6.881 Shepherd, J. D., and Bear, M. F. (2011). New views of Arc, a master regulator of Zagrebelsky, M., and Korte, M. (2014). Form follows function: BDNF and synaptic plasticity. Nat. Neurosci. 14, 279–284. doi: 10.1038/nn.2708 its involvement in sculpting the function and structure of synapses. Skerrett, R., Malm, T., and Landreth, G. (2014). Nuclear receptors in Neuropharmacology 76, 628–638. doi: 10.1016/j.neuropharm.2013.05.029 neurodegenerative diseases. Neurobiol. Dis. 72, 104–116. doi: 10.1016/j.nbd. Zetterström, R. H., Williams, R., Perlmann, T., and Olson, L. (1996). Cellular 2014.05.019 expression of the immediate early transcription factors Nurr1 and NGFI- Sleiman, P. M. A., Healy, D. G., Muqit, M. M. K., Yang, Y. X., Van Der Brug, B suggests a gene regulatory role in several brain regions including the M., Holton, J. L., et al. (2009). Characterisation of a novel NR4A2 mutation nigrostriatal dopamine system. Mol. Brain Res. 41, 111–120. doi: 10.1016/0169- in Parkinson’s disease brain. Neurosci. Lett. 457, 75–79. doi: 10.1016/j.neulet. 328x(96)00074-5 2009.03.021 Zhang, X., Odom, D. T., Koo, S.-H., Conkright, M. D., Canettieri, G., Best, J., Smith, G. A., Rocha, E. M., Rooney, T., Barneoud, P., McLean, J. R., Beagan, J., et al. et al. (2005). Genome-wide analysis of cAMP-response element binding protein (2015). A Nurr1 agonist causes neuroprotection in a Parkinson’s disease lesion occupancy, phosphorylation, and target gene activation in human tissues. Proc. model primed with the toll-like receptor 3 dsRNA inflammatory stimulant Natl. Acad. Sci. U.S.A. 102:4459. doi: 10.1073/pnas.0501076102 Poly(I:C). PLoS One 10:e0121072. doi: 10.1371/journal.pone.0121072 Zhang, Y., Chen, G., Gao, B., Li, Y., Liang, S., Wang, X., et al. (2016). NR4A1 Sousa, K. M., Mira, H., Hall, A. C., Jansson-Sjöstrand, L., Kusakabe, M., and Arenas, knockdown suppresses seizure activity by regulating surface expression of E. (2007). Microarray analyses support a role for Nurr1 in resistance to oxidative NR2B. Sci. Rep. 6:37713. stress and neuronal differentiation in neural stem cells. Stem Cells 25, 511–519. Zheng, K., Heydari, B., and Simon, D. K. (2003). A common NURR1 doi: 10.1634/stemcells.2006-0238 polymorphism associated with parkinson disease and diffuse lewy body disease. Swerdlow, N. R., and Geyer, M. A. (1998). Using an animal model of deficient Arch. Neurol. 60, 722–725. doi: 10.1001/archneur.60.5.722 sensorimotor gating to study the pathophysiology and new treatments of schizophrenia. Schizophrenia Bull. 24, 285–301. doi: 10.1093/oxfordjournals. Conflict of Interest: The authors declare that the research was conducted in the schbul.a033326 absence of any commercial or financial relationships that could be construed as a Terzioglu-Usak, S., Negis, Y., Karabulut, D. S., Zaim, M., and Isik, S. (2017). potential conflict of interest. Cellular model of Alzheimer’s disease: Aβ1-42 peptide induces amyloid deposition and a decrease in topo isomerase IIβ and Nurr1 expression. Curr. Publisher’s Note: All claims expressed in this article are solely those of the authors Alzheimer Res. 14, 636–644. doi: 10.2174/1567205014666170117103217 and do not necessarily represent those of their affiliated organizations, or those of Tokuoka, H., Hatanaka, T., Metzger, D., and Ichinose, H. (2014). Nurr1 the publisher, the editors and the reviewers. Any product that may be evaluated in expression is regulated by voltage-dependent calcium channels and calcineurin this article, or claim that may be made by its manufacturer, is not guaranteed or in cultured hippocampal neurons. Neurosci. Lett. 559, 50–55. doi: endorsed by the publisher. 10.1016/j.neulet.2013.11.033 Trachtenberg, J. T., Chen, B. E., Knott, G. W., Feng, G., Sanes, J. R., Welker, E., et al. Copyright © 2021 Català-Solsona, Miñano-Molina and Rodríguez-Álvarez. This (2002). Long-term in vivo imaging of experience-dependent synaptic plasticity is an open-access article distributed under the terms of the Creative Commons in adult cortex. Nature 420, 788–794. Attribution License (CC BY). The use, distribution or reproduction in other forums Uchida, S., and Shumyatsky, G. P. (2018). Synaptically localized transcriptional is permitted, provided the original author(s) and the copyright owner(s) are credited regulators in memory formation. Neuroscience 370, 4–13. and that the original publication in this journal is cited, in accordance with accepted Vecsey, C. G., Hawk, J. D., Lattal, K. M., Stein, J. M., Fabian, S. A., Attner, M. A., academic practice. No use, distribution or reproduction is permitted which does not et al. (2007). Histone deacetylase inhibitors enhance memory and synaptic comply with these terms. Frontiers in Molecular Neuroscience | www.frontiersin.org 13 November 2021 | Volume 14 | Article 786226