Retinoic acid regulates RAR -mediated control of translation in dendritic RNA granules during homeostatic synaptic plasticity

Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720-3200, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 11/2008; 105(41):16015-20. DOI: 10.1073/pnas.0804801105
Source: PubMed


Homeostatic plasticity is thought to play an important role in maintaining the stability of neuronal circuits. During one form of homeostatic plasticity, referred to as synaptic scaling, activity blockade leads to a compensatory increase in synaptic transmission by stimulating in dendrites the local translation and synaptic insertion of the AMPA receptor subunit GluR1. We have previously shown that all-trans retinoic acid (RA) mediates activity blockade-induced synaptic scaling by activating dendritic GluR1 synthesis and that this process requires RARalpha, a member of the nuclear RA receptor family. This result raised the question of where RARalpha is localized in dendrites and whether its localization is regulated by RA and/or activity blockade. Here, we show that activity blockade or RA treatment in neurons enhances the concentration of RARalpha in the dendritic RNA granules and activates local GluR1 synthesis in these RNA granules. Importantly, the same RNA granules that contain RARalpha also exhibit an accumulation of GluR1 protein but with a much slower time course than that of RARalpha, suggesting that the former regulates the latter. Taken together, our results provide a direct link between dendritically localized RARalpha and local GluR1 synthesis in RNA granules during RA-mediated synaptic signaling in homeostatic synaptic plasticity.

    • "Classically, RA influences gene expression by binding to nuclear hormone receptors, of which there are two main classes: the RA receptors (RARs) and retinoid X receptors (RXRs). A number of recent studies have, however, shown nonnuclear localization of RARs and RXRs (Carter et al. 2010Carter et al. , 2011Maghsoodi et al. 2008;Schrage et al. 2006), and others have described nongenomic actions of the retinoid receptors (Aoto et al. 2008;Carter et al. 2010;Liao et al. 2004;Liou et al. 2005;Poon and Chen 2008;Sarti et al. 2012Sarti et al. , 2013). Many of these studies described relatively rapid responses to RA, further supporting its role in nongenomic signaling. "
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    ABSTRACT: Retinoic acid, the active metabolite of Vitamin A, is important for nervous system development, regeneration as well as cognitive functions of the adult CNS. These CNS functions are all highly dependent on neuronal activity. Retinoic acid has previously been shown to induce changes in the firing properties and action potential waveforms of adult molluscan neurons in a dose- and isomer-dependent manner. In this study, we aimed to determine the cellular pathways by which retinoic acid might exert such effects, by testing the involvement of pathways previously shown to be affected by retinoic acid. We demonstrated that the ability of all-trans retinoic acid (atRA) to induce electrophysiological changes in cultured molluscan neurons was not prevented by inhibitors of protein synthesis, protein kinase A or phospholipase C. However, we showed that atRA was capable of rapidly reducing intracellular calcium levels in the same dose-and isomer-dependent manner as shown previously for changes in neuronal firing. Moreover, we also demonstrated that the transmembrane ion flux through voltage-gated calcium channels was rapidly modulated by retinoic acid. In particular, the peak current density was reduced and the inactivation rate was increased in the presence of atRA, over a similar time course as the changes in cell firing and reductions in intracellular calcium. These studies provide further evidence for the ability of atRA to induce rapid effects in mature neurons.
    No preview · Article · Oct 2014 · Journal of Neurophysiology
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    • "The intercellular signaling molecule RA has been found to regulate homeostatic synaptic plasticity in rodent neuronal cultures (Aoto et al., 2008; Maghsoodi et al., 2008; Soden and Chen, 2010; Chen et al., 2012). Here, RA was demonstrated to be required for the homeostatic increase in synaptic strength following postsynaptic receptor perturbation (Aoto et al., 2008). "
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    ABSTRACT: Homeostatic signaling systems are ubiquitous forms of biological regulation, having been studied for hundreds of years in the context of diverse physiological processes including body temperature and osmotic balance. However, only recently has this concept been brought to the study of excitatory and inhibitory electrical activity that the nervous system uses to establish and maintain stable communication. Synapses are a primary target of neuronal regulation with a variety of studies over the past 15 years demonstrating that these cellular junctions are under bidirectional homeostatic control. Recent work from an array of diverse systems and approaches has revealed exciting new links between homeostatic synaptic plasticity and a variety of seemingly disparate neurological and psychiatric diseases. These include autism spectrum disorders, intellectual disabilities, schizophrenia, and Fragile X Syndrome. Although the molecular mechanisms through which defective homeostatic signaling may lead to disease pathogenesis remain unclear, rapid progress is likely to be made in the coming years using a powerful combination of genetic, imaging, electrophysiological, and next generation sequencing approaches. Importantly, understanding homeostatic synaptic plasticity at a cellular and molecular level may lead to developments in new therapeutic innovations to treat these diseases. In this review we will examine recent studies that demonstrate homeostatic control of postsynaptic protein translation, retrograde signaling, and presynaptic function that may contribute to the etiology of complex neurological and psychiatric diseases.
    Full-text · Article · Nov 2013 · Frontiers in Cellular Neuroscience
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    • "We have shown here that RARa signalling modulates key physiological mechanisms involved in Ab clearance and how this signalling system is compromised by Ab, which reduces the synthesis of the endogenous ligand RA. As RA and the RARa system have been implicated as one mechanism contributing to homeostatic synaptic plasticity (Aoto et al., 2008; Chen et al., 2008; Maghsoodi et al., 2008; Sarti et al., 2012), the question should be raised as to whether Ab also participates in this regulatory mechanism, given that normally synaptic activity sets its extracellular level (Cirrito et al., 2005). There is evidence that endogenous Ab has a number of physiological roles, including neuronal survival (Plant et al., 2003), modifying the expression of potassium channels (Plant et al., 2006) and of the probability of transmitter release (Abramov et al., 2009) as well as being necessary for synaptic plasticity and memory (Puzzo et al., 2008, 2011); most of these effects may be achieved by the monomeric form of Ab. "
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    ABSTRACT: The retinoic acid receptor (RAR) α system plays a key role in the adult brain, participating in the homeostatic control of synaptic plasticity, essential for memory function. Here we show that RARα signalling is down-regulated by amyloid beta (Aβ), which inhibits the synthesis of the endogenous ligand, retinoic acid (RA). This results in the counteraction of a variety of RARα-activated pathways that are key in the aetiopathology of Alzheimer's disease (AD) but which can be reversed by an RARα agonist. RARα signalling improves cognition in the Tg2576 mice, it has an anti-inflammatory effect and promotes Aβ clearance by increasing insulin degrading enzyme and neprilysin activity in both microglia and neurons. In addition, RARα signalling prevents tau phosphorylation. Therefore, stimulation of the RARα signalling pathway using a synthetic agonist, by both clearing Aβ and counteracting some of its toxic effects, offers therapeutic potential for the treatment of AD.
    Full-text · Article · Feb 2013 · European Journal of Neuroscience
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