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

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 blockadeinduced synaptic scaling by activating dendritic GluR1 synthesis and that this process requires RAR␣, a member of the nuclear RA receptor family. This result raised the question of where RAR␣ 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 RAR␣ in the dendritic RNA granules and activates local GluR1 synthesis in these RNA granules. Importantly, the same RNA granules that contain RAR␣ also exhibit an accumulation of GluR1 protein but with a much slower time course than that of RAR␣, suggesting that the former regulates the latter. Taken together, our results provide a direct link between dendritically localized RAR␣ and local GluR1 synthesis in RNA granules during RA-mediated synaptic signaling in homeostatic synaptic plasticity.FMRP ͉ GluR1 ͉ local protein translation ͉ synaptic scaling H omeostatic synaptic plasticity plays important roles in maintaining the stability of neural networks through the adjustment of global synaptic strength (1, 2). A particular form of homeostatic plasticity, referred to as synaptic scaling, modifies all synapses onto a neuron concurrently in a multiplicative fashion, with greater synaptic adjustment at stronger synapses than at weaker ones, allowing global changes of synaptic activity while preserving relative synaptic strength between individual synapses (3, 4). One well characterized form of synaptic scaling is the increase in synaptic strength induced by chronic blockade of neuronal activity with tetradotoxin (TTX) and the NMDA receptor antagonist APV. This form of synaptic scaling, manifested by an increase in synaptic glutamate receptor response, is mediated by the local synthesis and synaptic insertion of homomeric GluR1 receptors (5-7).We recently found that all-trans retinoic acid (RA), the active form of retinoids in the brain, mediates activity blockade-induced synaptic scaling (8). We demonstrated that activity blockadewhich induces homeostatic plasticity-strongly stimulates neuronal RA synthesis, which in turn activates dendritic GluR1 synthesis. We thus described a function of RA as a synaptic signal that operates during homeostatic plasticity to up-regulate synaptic strength by increasing the size of the postsynaptic glutamate receptor response. Additionally, we suggested that RAR␣ may be critically involved in this form of RA signaling because RAR␣ is present in dendrites, and knocking down RAR␣ blocks synaptic scaling. These results were surprising, given our previous under...

Retinoic acid-gated sequence-specific translational control by RARα

“…Additionally, the use of an RAR␣ specific agonist recapitulated the effects on both synaptic scaling and local GluR1 synthesis (9). We also observed translation of GluR1 mRNA in dendritic RNA granules containing RAR␣ using immunogold electron microscopy (11). One of the most striking results in these studies was the ability of RA or an RAR␣ agonist to stimulate GluR1 protein synthesis in synaptoneurosomes, a biochemical preparation that lacks somatic components and thus operates in a transcriptionindependent manner.…”

“…We have previously established that dendritic RA signaling plays an important role in homeostatic synaptic plasticity, which occurs through RAR␣-mediated translational regulation in dendrites (9,11). As RNA binding proteins are integral to the intracellular sorting and translational control of mRNAs in dendrites (20), we speculated whether RAR␣ could directly associate with mRNAs.…”

A metaplasticity view of the interaction between homeostatic and Hebbian plasticity

“…B 372: 20160155 that regulates gene transcription during development [130]. In mature neurons, however, RARa can translocate out of the nucleus into neuronal dendrites and regulate translation of specific mRNAs located in RNA granules [131][132][133]. During homeostatic plasticity, RA synthesis and the translational regulation function of RARa lead to enhanced excitatory synaptic transmission and reduced inhibitory synaptic transmission [132][133][134].…”

β Ca 2+ /CaM-dependent kinase type II triggers upregulation of GluA1 to coordinate adaptation to synaptic inactivity in hippocampal neurons

“…This finding raises interesting questions about the mechanisms that link the very different modes of induction to their ultimate functional effects. Although α Ca 2+ /CaM-dependent kinase type II (αCaMKII) is generally accepted as a critical player in inducing LTP, a varied group of signaling molecules have been implicated in the response to chronic activity deprivation, including BDNF (4-7), Arc (8), TNF-α (9, 10), retinoic acid (11,12), and β3 integrin (13,14). The interrelationship between these putative signaling molecules and the overall organization of the signaling in response to prolonged activity block remain obscure.…”