Molecular Network and Chromosomal Clustering of Genes Involved in Synaptic Plasticity in the Hippocampus

Park, Chang Sin; Gong, Ruomu; Stuart, Joshua M.; Tang, Shao-Jun

doi:10.1074/jbc.m605876200

Cited by 72 publications

(70 citation statements)

References 80 publications

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“…1). This finding is consistent with several studies of memoryassociated gene expression, which indicate that many long-term memory associated genes are unregulated ∼1 h after behavioral treatments or LTP induction (Levenson et al 2004a;von Hertzen and Giese 2005;Park et al 2006). Furthermore, our earlier bioinformatics and expression array analysis showed that most memory-associated genes regulated at 1 h after behavioral training contain putative c-Rel elements in their DNA upstream regions, within 1 kb of their initiation start site.…”

Section: Discussionsupporting

confidence: 78%

c-Rel, an NF-κB family transcription factor, is required for hippocampal long-term synaptic plasticity and memory formation

et al. 2008

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Transcription is a critical component for consolidation of long-term memory. However, relatively few transcriptional mechanisms have been identified for the regulation of gene expression in memory formation. In the current study, we investigated the activity of one specific member of the NF-B transcription factor family, c-Rel, during memory consolidation. We found that contextual fear conditioning elicited a time-dependent increase in nuclear c-Rel levels in area CA1 and DG of hippocampus. These results suggest that c-rel is active in regulating transcription during memory consolidation. To identify the functional role of c-Rel in memory formation, we characterized c-rel −/− mice in several behavioral tasks. c-rel −/− mice displayed significant deficits in freezing behavior 24 h after training for contextual fear conditioning but showed normal freezing behavior in cued fear conditioning and in short-term contextual fear conditioning. In a novel object recognition test, wild-type littermate mice exhibited a significant preference for a novel object, but c-rel −/− mice did not. These results indicate that c-rel −/− mice have impaired hippocampus-dependent memory formation. To investigate the role of c-Rel in long-term synaptic plasticity, baseline synaptic transmission and long-term potentiation (LTP) at Schaffer collateral synapses in c-rel −/− mice was assessed. c-rel −/− slices had normal baseline synaptic transmission but exhibited significantly less LTP than did wild-type littermate slices. Together, our results demonstrate that c-Rel is necessary for long-term synaptic potentiation in vitro and hippocampus-dependent memory formation in vivo.Memory is a process through which learned information is stored, and newly formed memories are susceptible to disruption and must be stabilized for long-term storage through a process referred to as memory consolidation (McGaugh 2000). Consolidation of explicit long-term memory requires a series of hippocampus-dependent molecular processes, including gene transcription. The necessity for gene transcription to sustain longterm memory has been demonstrated in several animal models using transcription inhibitors (Thut and Lindell 1974;Kandel 2001). However, the identity and role of transcriptional mediators in long-term memory formation has yet to be fully addressed. So far, a relatively few transcription factors such as CREB, C/EBP, c-fos, and Zif268/egr-1 have been implicated in the consolidation of long-term memory (Yin et al. 1995;Jones et al. 2001;Chen et al. 2003;Fleischmann et al. 2003). Therefore in a previous study, we identified a list of candidate transcription factors that are potentially involved in the process of long-term memory consolidation using expression array profiling and a bioinformatics approach (Levenson et al. 2004a). Through these studies, the c-Rel transcription factor was identified as the most probable candidate for contributing to memory consolidation from among this novel list of transcription factors, because its DNA-binding motif is highly ...

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Section: Discussionsupporting

confidence: 78%

c-Rel, an NF-κB family transcription factor, is required for hippocampal long-term synaptic plasticity and memory formation

et al. 2008

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“…However, because of technical limitations, a genome-wide analysis of activity-dependent gene expression has only recently become possible. High-density oligonucleotide microarrays and differential analysis of library expression (DAzLE) have been used to identify genes in cortical and hippocampal neurons whose expression is acutely altered in response to membrane depolarization, NMDA application, LTP induction, and seizure induction (Altar et al 2004, Hong et al 2004, Park et al 2006. These experiments confirm the presence of several hundred neuronal activity-regulated genes in these cells.…”

Section: The Activity-regulated Gene Expression Program In Neurons: Gmentioning

confidence: 50%

Signaling Mechanisms Linking Neuronal Activity to Gene Expression and Plasticity of the Nervous System

Flavell

Greenberg

2008

Annu. Rev. Neurosci.

760

710

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Sensory experience and the resulting synaptic activity within the brain are critical for the proper development of neural circuits. Experience-driven synaptic activity causes membrane depolarization and calcium influx into select neurons within a neural circuit, which in turn trigger a wide variety of cellular changes that alter the synaptic connectivity within the neural circuit. One way in which calcium influx leads to the remodeling of synapses made by neurons is through the activation of new gene transcription. Recent studies have identified many of the signaling pathways that link neuronal activity to transcription, revealing both the transcription factors that mediate this process and the neuronal activity-regulated genes. These studies indicate that neuronal activity regulates a complex program of gene expression involved in many aspects of neuronal development, including dendritic branching, synapse maturation, and synapse elimination. Genetic mutations in several key regulators of activity-dependent transcription give rise to neurological disorders in humans, suggesting that future studies of this gene expression program will likely provide insight into the mechanisms by which the disruption of proper synapse development can give rise to a variety of neurological disorders.

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“…However, we found that after novel song exposure, declining RNAs (noveldown) actually outnumbered the increasing ones, and by a large margin (463 vs. 153). Comparatively little attention has been given to understanding the mechanism and function of experiencedependent gene suppression in the brain, despite prior evidence for it in the literature (24)(25)(26)(35)(36)(37). Here we detected enrichment for ion channel protein genes in the novel-down set, including channels for calcium, potassium, and sodium and the AMPA glutamate receptor.…”

Section: Auditory Lobulementioning

confidence: 68%

“…We confirmed the acute activation of familiar ''immediate early genes'' by novel birdsong (Table 2), but found that 20% of detectable transcripts (4,341 of 18,246 different probes) ultimately changed their expression in the 24 h following song exposure (considering both the novel and habituated treatment groups). This is an enormous increase over the number of gene products previously identified as ''activity regulated'' in the songbird brain, although it is not entirely unexpected on the basis of recent studies in rodents (24)(25)(26)(27). In the zebra finch, using a smaller microarray and extensive in situ hybridization analyses, Wada et al described 33 genes that are ''singing regulated'' in other parts of the brain responsible for song production (15).…”

Section: Discussionmentioning

confidence: 99%

Discrete molecular states in the brain accompany changing responses to a vocal signal

Dong¹,

Replogle

Hasadsri³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

100

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New experiences can trigger changes in gene expression in the brain. To understand this phenomenon better, we studied zebra finches hearing playbacks of birdsong. Earlier research had shown that initial playbacks of a novel song transiently increase the ZENK (ZIF-268, EGR1, NGFIA, KROX-24) mRNA in the auditory forebrain, but the response selectively habituates after repetition of the stimulus. Here, using DNA microarray analysis, we show that novel song exposure induces rapid changes in thousands of RNAs, with even more RNAs decreasing than increasing. Habituation training leads to the emergence of a different gene expression profile a day later, accompanied by loss of essentially all of the rapid ''novel'' molecular responses. The novel molecular profile is characterized by increases in genes involved in transcription and RNA processing and decreases in ion channels and putative noncoding RNAs. The ''habituated'' profile is dominated by changes in genes for mitochondrial proteins. A parallel proteomic analysis [2-dimensional difference gel electrophoresis (2D-DIGE) and sequencing by mass spectrometry] also detected changes in mitochondrial proteins, and direct enzyme assay demonstrated changes in both complexes I and IV in the habituated state. Thus a natural experience, in this case hearing the sound of birdsong, can lead to major shifts in energetics and macromolecular metabolism in higher centers in the brain.habituation ͉ microarray ͉ mitochondria ͉ proteomic ͉ songbird T he genome was once regarded as a passive agent in brain function, directing brain development but having little role in the moment-to-moment operation of the mature brain. Through the widespread application of technologies for measuring gene expression in experimental model systems, however, it now appears that changing social conditions, perceptual experience, and behavioral activity can all result in rapid changes in the expression of specific genes in the brain (1, 2). The challenge ahead is to understand the links between gene expression and natural experience, behavior, and cognition.A striking example for study is the phenomenon of song response habituation in songbirds (3). In one of the first demonstrations of brain gene activation in response to a natural experience, Mello and colleagues (4) showed that the sound of another bird singing triggers a transient increase in expression of the ZENK gene EGR1, NGFIA, in an auditory/associative region of the songbird forebrain. This was not simply a sensory or an auditory response, as its magnitude showed clear categorical discrimination (conspecific song Ͼ heterospecific song Ͼ noise Ͼ pure tones). Further research showed that the same song stimulus would either activate ZENK expression or not, depending on the recent history of exposure to the stimulus and its context. After the stimulus was repeated for a few hours the ZENK RNA declined back to its initial starting level (5, 6). Subsequent presentations no longer elicited a response, but presentation of a different song (6) or even of ...

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Molecular Network and Chromosomal Clustering of Genes Involved in Synaptic Plasticity in the Hippocampus

Cited by 72 publications

References 80 publications

c-Rel, an NF-κB family transcription factor, is required for hippocampal long-term synaptic plasticity and memory formation

c-Rel, an NF-κB family transcription factor, is required for hippocampal long-term synaptic plasticity and memory formation

Signaling Mechanisms Linking Neuronal Activity to Gene Expression and Plasticity of the Nervous System

Discrete molecular states in the brain accompany changing responses to a vocal signal

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