NMDA receptor-independent control of transcription factors and gene expression

Laboratory of Neurobiology, National Institute of Environmental Health Sciences, National Institutes of Health, NC 27709, USA.
Neuroreport (Impact Factor: 1.52). 09/2009; 20(16):1429-33. DOI: 10.1097/WNR.0b013e3283311db6
Source: PubMed


Consolidation of synaptic plasticity seems to require transcription, but how the nucleus is informed in this context remains unknown. As NMDA receptor antagonists have been shown to interfere with action potential generation, the issue of whether or not a synaptically generated signal is required for nuclear signaling is currently unresolved. Here, we show that pharmacological maintenance of action potentials during NMDA receptor blockade allows for NMDA receptor-independent transcription factor binding and arc gene expression, both of which were previously thought to be NMDA receptor dependent. These data suggest that types of signaling in the nucleus previously attributed to NMDA-receptor-dependent synapse-to-nucleus signals can be initiated in the absence of NMDA receptor-dependent synaptic plasticity.

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Available from: Eric Hudgins
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    • " voltage - dependent Ca 2+ channel , also regulate Arc expression ( Kakizawa et al . , 2000 ; Hashimoto et al . , 2011 ) . To our knowledge , this is the first study to suggest that the regulation of Arc expression through CB1R activity in neonatal and adult mice . Arc tran - scription is also regulated by voltage - sensitive calcium chan - nels ( Adams et al . , 2009 ) , which are negatively regulated by CB1R ( Basavarajappa and Arancio , 2008 ) . Our findings suggest that the ERK1 / 2 - pCREB - Arc pathway is involved in neuronal survival downstream of the CB1Rs in the developing brain and is compromised by ethanol treatment . It is possible that ethanol - induced suppression of the ERK1 / 2 - pCRE"
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    ABSTRACT: Ethanol exposure to rodents during postnatal day 7 (P7), which is comparable to the third trimester of human pregnancy, induces long-term potentiation and memory deficits. However, the molecular mechanisms underlying these deficits are still poorly understood. In the present study, we explored the potential role of epigenetic changes at cannabinoid type 1 (CB1R) exon1 and additional CB1R functions, which could promote memory deficits in animal models of fetal alcohol spectrum disorder. We found that ethanol treatment of P7 mice enhances acetylation of H4 on lysine 8 (H4K8ace) at CB1R exon1, CB1R binding as well as the CB1R agonist-stimulated GTPγS binding in the hippocampus and neocortex, two brain regions that are vulnerable to ethanol at P7 and are important for memory formation and storage, respectively. We also found that ethanol inhibits cyclic adenosine monophosphate response element-binding protein (CREB) phosphorylation and activity-regulated cytoskeleton-associated protein (Arc) expression in neonatal and adult mice. The blockade or genetic deletion of CB1Rs prior to ethanol treatment at P7 rescued CREB phosphorylation and Arc expression. CB1R knockout mice exhibited neither ethanol-induced neurodegeneration nor inhibition of CREB phosphorylation or Arc expression. However, both neonatal and adult mice did exhibit enhanced CREB phosphorylation and Arc protein expression. P7 ethanol-treated adult mice exhibited impaired spatial and social recognition memory, which were prevented by the pharmacological blockade or deletion of CB1Rs at P7. Together, these findings suggest that P7 ethanol treatment induces CB1R expression through epigenetic modification of the CB1R gene, and that the enhanced CB1R function induces pCREB, Arc, spatial, and social memory deficits in adult mice. © The Author 2015. Published by Oxford University Press on behalf of CINP.
    Full-text · Article · Oct 2014 · The International Journal of Neuropsychopharmacology
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    • "The transcription, translation, trafficking and turnover of Arc mRNA and protein are tightly regulated and vary according to cell and stimulus type. Within minutes of NMDA receptor (NMDAR) or voltage-gated calcium channel activation, a burst of Arc transcription is initiated in all principal fields of the hippocampus (Adams, Robinson, Hudgins, Wissink, & Dudek, 2009), lasting for hours in the dentate gyrus (Lyford et al., 1995), and subsiding more rapidly in pyramidal neurons (Guzowski et al., 1999). Resulting mRNA is trafficked and targeted to specific synapses in an NMDAR-dependent manner (Farris, Lewandowski, Cox, & Steward, 2014; Moga et al., 2004; Steward et al., 1998), and although it has been widely thought to target recently activated synapses, current evidence indicates that locally translated ARC preferentially accumulates at relatively less active synaptic sites (Okuno et al., 2012). "
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    ABSTRACT: Memory decline is a common feature of aging. Expression of the immediate-early gene Arc is necessary for normal long-term memory, and although experience dependent Arc transcription is reportedly reduced in the aged rat hippocampus, it has not been clear whether this effect is an invariant consequence of growing older, or a finding linked specifically to age-related memory impairment. Here we show that experience dependent Arc mRNA expression in the hippocampus fails selectively among aged rats with spatial memory deficits. While these findings are consistent with the possibility that blunted Arc transcription contributes to cognitive aging, we also found increased basal ARC protein levels in the CA1 field of the hippocampus in aged rats with memory impairment, together with a loss of the experience dependent increase observed in young and unimpaired aged rats. Follow-up analysis revealed that increased basal translation and blunted ubiquitin mediated degradation may contribute to increased basal ARC protein levels noted in memory impaired aged rats. These findings indicate that Arc expression is regulated at multiple levels, and that several of these mechanisms are altered in cognitively impaired aged rats. Defining the influence of these alterations on the spatial and temporal fidelity of synapse specific, memory-related plasticity in the aged hippocampus is an important challenge.
    Full-text · Article · Aug 2014 · Neurobiology of Learning and Memory
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    • "Thus, we considered the possibility that some Ca 2+ -dependent genes regulate CF synapse elimination in the cerebellum. We focused on an immediate early gene, Arc, because its expression is tightly coupled to neural activity downstream of multiple signaling pathways (Bramham et al., 2008; Shepherd and Bear, 2011), including Ca 2+ influx through VDCCs (Adams et al., 2009). Arc messenger RNA (mRNA) is detectable in PCs in the mouse cerebellum at an early postnatal stage, and its expression increases during postnatal development (Allen Brain Atlas; "
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    ABSTRACT: Neural circuits are shaped by activity-dependent elimination of redundant synapses during postnatal development. In many systems, postsynaptic activity is known to be crucial, but the precise mechanisms remain elusive. Here, we report that the immediate early gene Arc/Arg3.1 mediates elimination of surplus climbing fiber (CF) to Purkinje cell (PC) synapses in the developing cerebellum. CF synapse elimination was accelerated when activity of channelrhodopsin-2-expressing PCs was elevated by 2-day photostimulation. This acceleration was suppressed by PC-specific knockdown of either the P/Q-type voltage-dependent Ca(2+) channels (VDCCs) or Arc. PC-specific Arc knockdown had no appreciable effect until around postnatal day 11 but significantly impaired CF synapse elimination thereafter, leaving redundant CF terminals on PC somata. The effect of Arc knockdown was occluded by simultaneous knockdown of P/Q-type VDCCs in PCs. We conclude that Arc mediates the final stage of CF synapse elimination downstream of P/Q-type VDCCs by removing CF synapses from PC somata.
    Full-text · Article · Jun 2013 · Neuron
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