<i>Zif268</i>
            /
            <i>Egr1</i>
            gain of function facilitates hippocampal synaptic plasticity and long-term spatial recognition memory

Penke, Zsuzsa; Morice, Elise; Veyrac, Alexandra; Gros, Alexandra; Chagneau, Carine; Blanc, Pascale M. Le; Samson, Nathalie; Baumgärtel, Karsten; Mansuy, Isabelle M.; Davis, Sabrina; Laroche, Serge

doi:10.1098/rstb.2013.0159

Cited by 61 publications

(54 citation statements)

References 46 publications

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“…Consistent with its function as an immediate-early gene, biophysical characteristics of Egr1 include fast (millisecond) activation in response to stimuli and transient expression (Veyrac et al, 2014). Egr1 is implicated in synaptic transmission (Jones et al, 2001; Penke et al, 2013), learning (Guzowski et al, 2001), memory consolidation (Jones et al, 2001; Penke et al, 2013; although see Lee et al, 2004) and reconsolidation (Lee et al, 2004), and more recently in the recruitment of new neurons into functional networks after hippocampal neurogenesis (Veyrac et al, 2013). Coincident with these roles, levels of Egr1 protein are higher in brain regions involved in these functions, including the hippocampus, particularly the CA1 region, and cortex relative to other regions (Beckmann and Wilce, 1997).…”

Section: Early Growth Response (Egr) Factorsmentioning

confidence: 99%

Neuronal Gene Targets of NF-κB and Their Dysregulation in Alzheimer's Disease

Snow

Albensi

2016

Front. Mol. Neurosci.

136

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Although, better known for its role in inflammation, the transcription factor nuclear factor kappa B (NF-κB) has more recently been implicated in synaptic plasticity, learning, and memory. This has been, in part, to the discovery of its localization not just in glia, cells that are integral to mediating the inflammatory process in the brain, but also neurons. Several effectors of neuronal NF-κB have been identified, including calcium, inflammatory cytokines (i.e., tumor necrosis factor alpha), and the induction of experimental paradigms thought to reflect learning and memory at the cellular level (i.e., long-term potentiation). NF-κB is also activated after learning and memory formation in vivo. In turn, activation of NF-κB can elicit either suppression or activation of other genes. Studies are only beginning to elucidate the multitude of neuronal gene targets of NF-κB in the normal brain, but research to date has confirmed targets involved in a wide array of cellular processes, including cell signaling and growth, neurotransmission, redox signaling, and gene regulation. Further, several lines of research confirm dysregulation of NF-κB in Alzheimer's disease (AD), a disorder characterized clinically by a profound deficit in the ability to form new memories. AD-related neuropathology includes the characteristic amyloid beta plaque formation and neurofibrillary tangles. Although, such neuropathological findings have been hypothesized to contribute to memory deficits in AD, research has identified perturbations at the cellular and synaptic level that occur even prior to more gross pathologies, including transcriptional dysregulation. Indeed, synaptic disturbances appear to be a significant correlate of cognitive deficits in AD. Given the more recently identified role for NF-κB in memory and synaptic transmission in the normal brain, the expansive network of gene targets of NF-κB, and its dysregulation in AD, a thorough understanding of NF-κB-related signaling in AD is warranted and may have important implications for uncovering treatments for the disease. This review aims to provide a comprehensive view of our current understanding of the gene targets of this transcription factor in neurons in the intact brain and provide an overview of studies investigating NF-κB signaling, including its downstream targets, in the AD brain as a means of uncovering the basic physiological mechanisms by which memory becomes fragile in the disease.

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Section: Early Growth Response (Egr) Factorsmentioning

confidence: 99%

Neuronal Gene Targets of NF-κB and Their Dysregulation in Alzheimer's Disease

Snow

Albensi

2016

Front. Mol. Neurosci.

136

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“…44 The enhancement in the levels of Arc and Egr1 mRNAs by CTX 3C was indicative of an increase in synaptic activity. These IEGs are implicated in the molecular mechanisms of homeostatic plasticity, 20,38 and it has been reported that Arc mediates the homeostatic response to increased activity by a pathway that ultimately downscales excitatory synaptic strength. 45 For the purpose of evaluating the effect of CTX 3C on mEPSCs, these events (isolated as described in the Materials and Methods section) were analyzed in control neurons and in neurons treated with 5 nM CTX 3C ( Figure 5).…”

Section: Ctx 3c Enhances the Expression Of Arc And Egr1mentioning

confidence: 99%

Chronic Ciguatoxin Treatment Induces Synaptic Scaling through Voltage Gated Sodium Channels in Cortical Neurons

Martı́n

Vale

Rubiolo

et al. 2015

Chem. Res. Toxicol.

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Ciguatoxins are sodium channels activators that cause ciguatera, one of the most widespread nonbacterial forms of food poisoning, which presents with long-term neurological alterations. In central neurons, chronic perturbations in activity induce homeostatic synaptic mechanisms that adjust the strength of excitatory synapses and modulate glutamate receptor expression in order to stabilize the overall activity. Immediate early genes, such as Arc and Egr1, are induced in response to activity changes and underlie the trafficking of glutamate receptors during neuronal homeostasis. To better understand the long lasting neurological consequences of ciguatera, it is important to establish the role that chronic changes in activity produced by ciguatoxins represent to central neurons. Here, the effect of a 30 min exposure of 10-13 days in vitro (DIV) cortical neurons to the synthetic ciguatoxin CTX 3C on Arc and Egr1 expression was evaluated using real-time polymerase chain reaction approaches. Since the toxin increased the mRNA levels of both Arc and Egr1, the effect of CTX 3C in NaV channels, membrane potential, firing activity, miniature excitatory postsynaptic currents (mEPSCs), and glutamate receptors expression in cortical neurons after a 24 h exposure was evaluated using electrophysiological and western blot approaches. The data presented here show that CTX 3C induced an upregulation of Arc and Egr1 that was prevented by previous coincubation of the neurons with the NaV channel blocker tetrodotoxin. In addition, chronic CTX 3C caused a concentration-dependent shift in the activation voltage of NaV channels to more negative potentials and produced membrane potential depolarization. Moreover, 24 h treatment of cortical neurons with 5 nM CTX 3C decreased neuronal firing and induced synaptic scaling mechanisms, as evidenced by a decrease in the amplitude of mEPSCs and downregulation in the protein level of glutamate receptors that was also prevented by tetrodotoxin. These findings identify an unanticipated role for ciguatoxin in the regulation of homeostatic plasticity in central neurons involving NaV channels and raise the possibility that some of the neurological symptoms of ciguatera might be explained by these compensatory mechanisms.

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“…Our results show for the first time, that GNX-induced impairments in the spontaneous object recognition test can be prevented by viral-mediated Zif268 expression. Mice with genetically-induced forebrain overexpression of Zif268 exhibit enhanced long-term object-location recognition as compared to controls (Penke et al, 2014). In the present study, we observed no enhancement of novel object preference in males that were gonadally intact and received mPFC AAV-Zif268 construct.…”

Section: Discussionmentioning

confidence: 99%

“…Loss-of-function studies have demonstrated the necessity of Zif268 gene expression for normal long-term memory formation (Jones et al, 2001, Bozon et al, 2002). In parallel, gain-of-function studies have shown that overexpression of Zif268 within the dentate gyrus can enhance long-term spatial memory (Penke et al, 2014). Within the neural circuitry that supports learning and memory, Zif268 expression is induced following learning-related stimuli.…”

Section: Introductionmentioning

confidence: 99%

“…As such, we used the y-maze to investigate working memory since mPFC integrity is required in this type of memory task (Yang et al, 2014). Furthermore, since Zif268 plays a major role in long-term memory (e.g., Penke et al, 2014), and the mPFC contributes to memory tasks without a spatial component (Barker et al, 2007; Barbosa et al, 2013), another aim of this work was to examine the role of mPFC Zif268 in long-term memory, investigated using the spontaneous object recognition (SOR; also known as: novel object recognition) test (Winters et al, 2010). Also, in order to investigate the impact of GNX on social anxiety-like behavior we employed the social interaction test.…”

Section: Introductionmentioning

confidence: 99%

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Viral-mediated Zif268 expression in the prefrontal cortex protects against gonadectomy-induced working memory, long-term memory, and social interaction deficits in male rats

et al. 2017

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In humans, some males experience reductions in testosterone levels, as a natural consequence of aging or in the clinical condition termed hypogonadism, which are associated with impaired cognitive performance and mood disorder(s). Some of these behavioral deficits can be reversed by testosterone treatment. Our previous work in rats reported that sex differences in the expression of the transcription factor Zif268, a downstream target of testosterone, within the medial prefrontal cortex (mPFC) mediates sex differences in social interaction. In the present study, we aimed to examine the effects of gonadectomy (GNX) in male rats on mPFC Zif268 expression, mood and cognitive behaviors. We also examined whether reinstitution of Zif268 in GNX rats will correct some of the behavioral deficits observed following GNX. Our results show that GNX induced a downregulation of Zif268 protein in the mPFC, which was concomitant with impaired memory in the y-maze and spontaneous object recognition test, reduced social interaction time, and depression-like behaviors in the forced swim test. Reinstitution of mPFC Zif268, using a novel adeno-associated-viral (AAV) construct, abrogated GNX-induced working memory and long-term memory impairments, and reductions in social interaction time, but not GNX-induced depression-like behaviors. These findings suggest that mPFC Zif268 exerts beneficial effects on memory and social interaction, and could be a potential target for novel treatments for behavioral impairments observed in hypogonadal and aged men with declining levels of gonadal hormones.

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Zif268 / Egr1 gain of function facilitates hippocampal synaptic plasticity and long-term spatial recognition memory

Cited by 61 publications

References 46 publications

Neuronal Gene Targets of NF-κB and Their Dysregulation in Alzheimer's Disease

Neuronal Gene Targets of NF-κB and Their Dysregulation in Alzheimer's Disease

Chronic Ciguatoxin Treatment Induces Synaptic Scaling through Voltage Gated Sodium Channels in Cortical Neurons

Viral-mediated Zif268 expression in the prefrontal cortex protects against gonadectomy-induced working memory, long-term memory, and social interaction deficits in male rats

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