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

ABSTRACT 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.

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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.
    Frontiers in Cellular Neuroscience 11/2013; 7:223. DOI:10.3389/fncel.2013.00223 · 4.29 Impact Factor
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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.
    European Journal of Neuroscience 02/2013; 37(7). DOI:10.1111/ejn.12142 · 3.18 Impact Factor
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    • "While alterations in postsynaptic firing have been shown to exert cell-wide homeostatic changes in synaptic strength (Ibata et al., 2008; Goold and Nicoll, 2010), several groups have demonstrated that compensatory synaptic adaptations can also be implemented locally in dendrites (Sutton et al., 2006; Aoto et al., 2008; Jakawich et al., 2010), even at individual synapses (Lee et al., 2010; Béïque et al., 2011; Hou et al., 2011). Indeed, acute loss of excitatory synaptic input induces a rapid and local recruitment of GluA1 homomeric receptors to affected synapses which is critically dependent on dendritic protein synthesis (Sutton et al., 2006; Aoto et al., 2008; Maghsoodi et al., 2008). In hippocampal neurons, this rapid postsynaptic compensation can be induced by blockade of either AMPARs or NMDARs, whereas retrograde compensation of presynaptic terminals accompanies AMPAR blockade but not NMDAR blockade (Jakawich et al., 2010). "
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    ABSTRACT: Mutations that alter signaling through the mammalian target of rapamycin complex 1 (mTORC1), a well established regulator of neuronal protein synthesis, have been linked to autism and cognitive dysfunction. Although previous studies have established a role for mTORC1 as necessary for enduring changes in postsynaptic function, here we demonstrate that dendritic mTORC1 activation in rat hippocampal neurons also drives a retrograde signaling mechanism promoting enhanced neurotransmitter release from apposed presynaptic terminals. This novel mode of synaptic regulation conferred by dendritic mTORC1 is locally implemented, requires downstream synthesis of brain-derived neurotrophic factor as a retrograde messenger, and is engaged in an activity-dependent fashion to support homeostatic trans-synaptic control of presynaptic function. Our findings thus reveal that mTORC1-dependent translation in dendrites subserves a unique mode of synaptic regulation, highlighting an alternative regulatory pathway that could contribute to the social and cognitive dysfunction that accompanies dysregulated mTORC1 signaling.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 11/2012; 32(48):17128-42. DOI:10.1523/JNEUROSCI.2149-12.2012 · 6.34 Impact Factor
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