Initiated by CREB: Resolving Gene Regulatory Programs in Learning and Memory

Kaldun, Jenifer C.; Sprecher, Simon G.

doi:10.1002/bies.201900045

Cited by 41 publications

(18 citation statements)

References 134 publications

(364 reference statements)

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“…CREB has been extensively studied in the brain since it is involved in a variety of relevant processes such as learning and memory or neuronal survival, among others ( Benito and Barco, 2015 ). For example, it is known that CREB activity is crucial for the maintenance of long-term plasticity and memory formation ( Bourtchuladze et al, 1994 ; Bartsch et al, 1998 ; Kaldun and Sprecher, 2019 ). Moreover, the genetic program downstream CREB is complex and different transcriptional programs could be elicited depending on the triggering stimulus, cellular context, and upstream signaling events ( Nonaka et al, 2014 ).…”

Section: Nr4a2 Transcription Factormentioning

confidence: 99%

Nr4a2 Transcription Factor in Hippocampal Synaptic Plasticity, Memory and Cognitive Dysfunction: A Perspective Review

Català-Solsona

Miñano-Molina

Rodríguez‐Álvarez

2021

Front. Mol. Neurosci.

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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, transcription factors have emerged as pivotal players underlying synaptic plasticity and the modification of neural networks required for memory formation and consolidation. Hippocampal synaptic dysfunction is widely accepted to underlie the cognitive decline observed in some neurodegenerative disorders including Alzheimer’s disease. Therefore, understanding the molecular pathways regulating gene expression profiles may help to identify new synaptic therapeutic targets. The nuclear receptor 4A subfamily (Nr4a) of transcription factors has been involved in a variety of physiological processes within the hippocampus, ranging from inflammation to neuroprotection. Recent studies have also pointed out a role for the activity-dependent nuclear receptor subfamily 4, group A, member 2 (Nr4a2/Nurr1) in hippocampal synaptic plasticity and cognitive functions, although the underlying molecular mechanisms are still poorly understood. In this review, we highlight the specific effects of Nr4a2 in hippocampal synaptic plasticity and memory formation and we discuss whether the dysregulation of this transcription factor could contribute to hippocampal synaptic dysfunction, altogether suggesting the possibility that Nr4a2 may emerge as a novel synaptic therapeutic target in brain pathologies associated to cognitive dysfunctions.

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Section: Nr4a2 Transcription Factormentioning

confidence: 99%

Nr4a2 Transcription Factor in Hippocampal Synaptic Plasticity, Memory and Cognitive Dysfunction: A Perspective Review

Català-Solsona

Miñano-Molina

Rodríguez‐Álvarez

2021

Front. Mol. Neurosci.

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“…After analyzing the modulation level of CREB, we further asked which signaling pathways are involved in the observed CREB phosphorylation in the nucleus accumbens during relief learning. Several studies demonstrated that CREB phosphorylation at Ser-133 may occur through any of its upstream protein kinases including protein kinase A (PKA), Ca 2+ -calmodulin-dependent kinases (CaMK), protein kinase B (PKB or Akt) extracellular-Signal-regulated kinase (ERK) or mitogen-activated protein kinase (MAPK) protein kinase C (PKC), p90 ribosomal S6 kinase (p90RSK), casein kinase I, and casein kinase II [12,13,32]. Based on previous studies, NMDAR induction plays a critical role in relief acquisition [9,10] and is able to stimulate CREB activity through different pathways [17,18,33].…”

Section: Discussionmentioning

confidence: 99%

“…A key protein in synaptic plasticity and memory is the cAMP response elementbinding protein (CREB) which functions as a transcriptional activator after its phosphorylation [11]. Previous studies in hippocampus-dependent contextual fear learning showed a biphasic pattern for CREB phosphorylation in long-term memory formation [12][13][14]. In the first phase (within 1 h after conditioning) CREB phosphorylation is likely to be stress-related and can trigger transcription of immediate early genes.…”

Section: Introductionmentioning

confidence: 99%

Regulation of CREB Phosphorylation in Nucleus Accumbens after Relief Conditioning

Soleimanpour

Acosta

Landgraf

et al. 2021

Cells

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Relief learning is the association of environmental cues with the cessation of aversive events. While there is increasing knowledge about the neural circuitry mediating relief learning, the respective molecular pathways are not known. Therefore, the aim of the present study was to examine different putative molecular pathways underlying relief learning. To this purpose, male rats were subjected either to relief conditioning or to a pseudo conditioning procedure. Forty-five minutes or 6 h after conditioning, samples of five different brain regions, namely the prefrontal cortex, nucleus accumbens (NAC), dorsal striatum, dorsal hippocampus, and amygdala, were collected. Using quantitative Western blots, the expression level of CREB, pCREB, ERK1/2, pERK1/2, CaMKIIα, MAP2K, PKA, pPKA, Akt, pAkt, DARPP-32, pDARPP-32, 14-3-3, and neuroligin2 were studied. Our analyses revealed that relief conditioned rats had higher CREB phosphorylation in NAC 6 h after conditioning than pseudo conditioned rats. The data further revealed that this CREB phosphorylation was mainly induced by dopamine D1 receptor-mediated activation of PKA, however, other kinases, downstream of the NMDA receptor, may also contribute. Taken together, the present study suggests that CREB phosphorylation, induced by a combination of different molecular pathways downstream of dopamine D1 and NMDA receptors, is essential for the acquisition and consolidation of relief learning.

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“…CREB also plays a role in synaptic plasticity and acts as a transcription factor of immediate-early genes (IEGs) related to synaptic plasticity (Kaldun & Sprecher, 2019). Arc is one of these target IEGs;…”

Section: Dopamine Biosynthetic Process 1 Daomentioning

confidence: 99%

Identification of gene targets of developmental neurotoxicity focusing on DNA hypermethylation involved in irreversible disruption of hippocampal neurogenesis in rats

Kikuchi

Takahashi

Ojiro

et al. 2020

J of Applied Toxicology

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We have previously found that maternal exposure to 6‐propyl‐2‐thiouracil (PTU), valproic acid (VPA), or glycidol (GLY) has a sustained or late effect on hippocampal neurogenesis at the adult stage in rat offspring. Herein, we searched for genes with hypermethylated promoter region and downregulated transcript level to reveal irreversible markers of developmental neurotoxicity. The hippocampal dentate gyrus of male rat offspring exposed maternally to PTU, VPA, or GLY was subjected to Methyl‐Seq and RNA‐Seq analyses on postnatal day (PND) 21. Among the genes identified, 170 were selected for further validation analysis of gene expression on PND 21 and PND 77 by real‐time reverse transcription‐PCR. PTU and GLY downregulated many genes on PND 21, reflecting diverse effects on neurogenesis. Furthermore, genes showing sustained downregulation were found after PTU or VPA exposure, reflecting a sustained or late effect on neurogenesis by these compounds. In contrast, such genes were not observed with GLY, probably because of the reversible nature of the effects. Among the genes showing sustained downregulation, Creb, Arc, and Hes5 were concurrently downregulated by PTU, suggesting an association with neuronal mismigration, suppressed synaptic plasticity, and reduction in neural stem and progenitor cells. Epha7 and Pvalb were also concurrently downregulated by PTU, suggesting an association with the reduction in late‐stage progenitor cells. VPA induced sustained downregulation of Vgf and Dpysl4, which may be related to the aberrations in synaptic plasticity. The genes showing sustained downregulation may be irreversible markers of developmental neurotoxicity.

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Initiated by CREB: Resolving Gene Regulatory Programs in Learning and Memory

Cited by 41 publications

References 134 publications

Nr4a2 Transcription Factor in Hippocampal Synaptic Plasticity, Memory and Cognitive Dysfunction: A Perspective Review

Nr4a2 Transcription Factor in Hippocampal Synaptic Plasticity, Memory and Cognitive Dysfunction: A Perspective Review

Regulation of CREB Phosphorylation in Nucleus Accumbens after Relief Conditioning

Identification of gene targets of developmental neurotoxicity focusing on DNA hypermethylation involved in irreversible disruption of hippocampal neurogenesis in rats

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