FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2050519369> ?p ?o ?g. }

• W2050519369 endingPage "320" @default.
• W2050519369 startingPage "308" @default.
• W2050519369 abstract "Normal brain function requires that the overall synaptic activity in neural circuits be kept constant. Long-term alterations of neural activity lead to homeostatic regulation of synaptic strength by a process known as synaptic scaling. The molecular mechanisms underlying synaptic scaling are largely unknown. Here, we report that all-trans retinoic acid (RA), a well-known developmental morphogen, unexpectedly mediates synaptic scaling in response to activity blockade. We show that activity blockade increases RA synthesis in neurons and that acute RA treatment enhances synaptic transmission. The RA-induced increase in synaptic strength is occluded by activity blockade-induced synaptic scaling. Suppression of RA synthesis prevents synaptic scaling. This form of RA signaling operates via a translation-dependent but transcription-independent mechanism, causes an upregulation of postsynaptic glutamate receptor levels, and requires RARα receptors. Together, our data suggest that RA functions in homeostatic plasticity as a signaling molecule that increases synaptic strength by a protein synthesis-dependent mechanism. Normal brain function requires that the overall synaptic activity in neural circuits be kept constant. Long-term alterations of neural activity lead to homeostatic regulation of synaptic strength by a process known as synaptic scaling. The molecular mechanisms underlying synaptic scaling are largely unknown. Here, we report that all-trans retinoic acid (RA), a well-known developmental morphogen, unexpectedly mediates synaptic scaling in response to activity blockade. We show that activity blockade increases RA synthesis in neurons and that acute RA treatment enhances synaptic transmission. The RA-induced increase in synaptic strength is occluded by activity blockade-induced synaptic scaling. Suppression of RA synthesis prevents synaptic scaling. This form of RA signaling operates via a translation-dependent but transcription-independent mechanism, causes an upregulation of postsynaptic glutamate receptor levels, and requires RARα receptors. Together, our data suggest that RA functions in homeostatic plasticity as a signaling molecule that increases synaptic strength by a protein synthesis-dependent mechanism. Normal nervous system function requires that neurons maintain a constant overall activity level and maintain a balance between the relative strength of individual synapses. Constant neural activity levels are achieved by synaptic scaling, a form of homeostatic synaptic plasticity (Davis, 2006Davis G.W. Homeostatic control of neural activity: from phenomenology to molecular design.Annu. Rev. Neurosci. 2006; 29: 307-323Crossref PubMed Scopus (395) Google Scholar, Turrigiano and Nelson, 2004Turrigiano G.G. Nelson S.B. Homeostatic plasticity in the developing nervous system.Nat. Rev. Neurosci. 2004; 5: 97-107Crossref PubMed Scopus (1600) Google Scholar). In synaptic scaling, all synapses of a neuron are modified concurrently in a multiplicative fashion with greater synaptic adjustment to stronger synapses, thereby preserving the relative synaptic weights of the overall circuit (Thiagarajan et al., 2005Thiagarajan T.C. Lindskog M. Tsien R.W. Adaptation to synaptic inactivity in hippocampal neurons.Neuron. 2005; 47: 725-737Abstract Full Text Full Text PDF PubMed Scopus (383) Google Scholar, Turrigiano et al., 1998Turrigiano G.G. Leslie K.R. Desai N.S. Rutherford L.C. Nelson S.B. Activity-dependent scaling of quantal amplitude in neocortical neurons.Nature. 1998; 391: 892-896Crossref PubMed Scopus (1529) Google Scholar) (but see Echegoyen et al., 2007Echegoyen J. Neu A. Graber K.D. Soltesz I. Homeostatic plasticity studied using in vivo hippocampal activity-blockade: synaptic scaling, intrinsic plasticity and age-dependence.PLoS ONE. 2007; 2: e700Crossref PubMed Scopus (99) Google Scholar). Several signaling pathways have been shown to mediate various forms of homeostatic synaptic plasticity in the mammalian central nervous system and the Drosophila neuromuscular junction. A decrease in neuronal activity, for instance, has been shown to decrease the ratio of α/β-CaMKII protein in neurons, likely by upregulating transcription of β-CaMKII (Thiagarajan et al., 2002Thiagarajan T.C. Piedras-Renteria E.S. Tsien R.W. alpha- and betaCaMKII. Inverse regulation by neuronal activity and opposing effects on synaptic strength.Neuron. 2002; 36: 1103-1114Abstract Full Text Full Text PDF PubMed Scopus (229) Google Scholar). The level of Arc/Arg3.1, an immediate-early gene that is rapidly induced by neuronal activity associated with information encoding in the brain (Guzowski et al., 2005Guzowski J.F. Timlin J.A. Roysam B. McNaughton B.L. Worley P.F. Barnes C.A. Mapping behaviorally relevant neural circuits with immediate-early gene expression.Curr. Opin. Neurobiol. 2005; 15: 599-606Crossref PubMed Scopus (270) Google Scholar), modulates homeostatic plasticity through a direct interaction with the endocytic pathway (Shepherd et al., 2006Shepherd J.D. Rumbaugh G. Wu J. Chowdhury S. Plath N. Kuhl D. Huganir R.L. Worley P.F. Arc/Arg3.1 mediates homeostatic synaptic scaling of AMPA receptors.Neuron. 2006; 52: 475-484Abstract Full Text Full Text PDF PubMed Scopus (535) Google Scholar). At the Drosophila neuromuscular junction, homeostatic synaptic growth is regulated by TGF-β, a synaptically released growth factor (Sweeney and Davis, 2002Sweeney S.T. Davis G.W. Unrestricted synaptic growth in spinster-a late endosomal protein implicated in TGF-beta-mediated synaptic growth regulation.Neuron. 2002; 36: 403-416Abstract Full Text Full Text PDF PubMed Scopus (197) Google Scholar). In addition to these neuron/muscle-autonomous factors, glia-derived factors such as the cytokine TNFα were demonstrated to control synaptic strength and to influence homeostatic synaptic plasticity (Beattie et al., 2002Beattie E.C. Stellwagen D. Morishita W. Bresnahan J.C. Ha B.K. Von Zastrow M. Beattie M.S. Malenka R.C. Control of synaptic strength by glial TNFalpha.Science. 2002; 295: 2282-2285Crossref PubMed Scopus (991) Google Scholar, Stellwagen and Malenka, 2006Stellwagen D. Malenka R.C. Synaptic scaling mediated by glial TNF-alpha.Nature. 2006; 440: 1054-1059Crossref PubMed Scopus (1148) Google Scholar). One particularly well-characterized form of homeostatic plasticity is the increase in synaptic strength induced by chronic blockade of neuronal activity with tetrodotoxin (TTX) and the NMDA receptor antagonist APV. A series of recent studies indicate that this form of homeostatic plasticity is mediated by the local synthesis and synaptic insertion of homomeric GluR1 receptors, which results in an increase of synaptic glutamate receptor response as manifested in an enhanced amplitude of unitary spontaneous miniature EPSCs (Ju et al., 2004Ju W. Morishita W. Tsui J. Gaietta G. Deerinck T.J. Adams S.R. Garner C.C. Tsien R.Y. Ellisman M.H. Malenka R.C. Activity-dependent regulation of dendritic synthesis and trafficking of AMPA receptors.Nat. Neurosci. 2004; 7: 244-253Crossref PubMed Scopus (411) Google Scholar, Sutton et al., 2004Sutton M.A. Wall N.R. Aakalu G.N. Schuman E.M. Regulation of dendritic protein synthesis by miniature synaptic events.Science. 2004; 304: 1979-1983Crossref PubMed Scopus (198) Google Scholar, Sutton et al., 2006Sutton M.A. Ito H.T. Cressy P. Kempf C. Woo J.C. Schuman E.M. Miniature neurotransmission stabilizes synaptic function via tonic suppression of local dendritic protein synthesis.Cell. 2006; 125: 785-799Abstract Full Text Full Text PDF PubMed Scopus (455) Google Scholar). Although several biochemical signaling pathways that trigger dendritic protein synthesis upon increase in neuronal activity have been identified (Kelleher et al., 2004Kelleher 3rd, R.J. Govindarajan A. Jung H.Y. Kang H. Tonegawa S. Translational control by MAPK signaling in long-term synaptic plasticity and memory.Cell. 2004; 116: 467-479Abstract Full Text Full Text PDF PubMed Scopus (662) Google Scholar, Klann and Dever, 2004Klann E. Dever T.E. Biochemical mechanisms for translational regulation in synaptic plasticity.Nat. Rev. Neurosci. 2004; 5: 931-942Crossref PubMed Scopus (324) Google Scholar, Schuman et al., 2006Schuman E.M. Dynes J.L. Steward O. Synaptic regulation of translation of dendritic mRNAs.J. Neurosci. 2006; 26: 7143-7146Crossref PubMed Scopus (181) Google Scholar), signaling pathways involved in this type of inactivity-induced synaptic scaling remain to be determined. During development, all-trans retinoic acid (RA) regulates gene transcription by binding to retinoic acid receptor (RAR) proteins, which are well-characterized transcription factors of the nuclear receptor family. In the nervous system, RA signaling is involved in neurogenesis and neuronal differentiation. Increasing evidence indicates that RA signaling may also play an important role in the mature brain (Lane and Bailey, 2005Lane M.A. Bailey S.J. Role of retinoid signalling in the adult brain.Prog. Neurobiol. 2005; 75: 275-293Crossref PubMed Scopus (280) Google Scholar). Specifically, RA is rapidly synthesized in various regions of the adult brain (Dev et al., 1993Dev S. Adler A.J. Edwards R.B. Adult rabbit brain synthesizes retinoic acid.Brain Res. 1993; 632: 325-328Crossref PubMed Scopus (47) Google Scholar). Deficiencies in retinoid metabolism and signaling cause impaired synaptic plasticity and learning (Chiang et al., 1998Chiang M.Y. Misner D. Kempermann G. Schikorski T. Giguere V. Sucov H.M. Gage F.H. Stevens C.F. Evans R.M. An essential role for retinoid receptors RARbeta and RXRgamma in long-term potentiation and depression.Neuron. 1998; 21: 1353-1361Abstract Full Text Full Text PDF PubMed Scopus (265) Google Scholar, Cocco et al., 2002Cocco S. Diaz G. Stancampiano R. Diana A. Carta M. Curreli R. Sarais L. Fadda F. Vitamin A deficiency produces spatial learning and memory impairment in rats.Neuroscience. 2002; 115: 475-482Crossref PubMed Scopus (169) Google Scholar, Misner et al., 2001Misner D.L. Jacobs S. Shimizu Y. de Urquiza A.M. Solomin L. Perlmann T. De Luca L.M. Stevens C.F. Evans R.M. Vitamin A deprivation results in reversible loss of hippocampal long-term synaptic plasticity.Proc. Natl. Acad. Sci. USA. 2001; 98: 11714-11719Crossref PubMed Scopus (211) Google Scholar) and may result in neurological diseases (Lane and Bailey, 2005Lane M.A. Bailey S.J. Role of retinoid signalling in the adult brain.Prog. Neurobiol. 2005; 75: 275-293Crossref PubMed Scopus (280) Google Scholar). Consistent with the notion that RA may have a role in the postmitotic properties of neurons, a recent study suggested that RA induces spine formation in cultured neurons by binding to a novel, cell surface-exposed variant of the RA-receptor RARα (Chen and Napoli, 2008Chen N. Napoli J.L. All-trans-retinoic acid stimulates translation and induces spine formation in hippocampal neurons through a membrane-associated RARalpha.FASEB J. 2008; 22: 236-245Crossref PubMed Scopus (124) Google Scholar). Here, we report that RA is a potent regulator of synaptic strength in cultured neurons and brain slices. We demonstrate that activity blockade—which induces homeostatic plasticity—strongly stimulates neuronal RA synthesis. We also show that RA rapidly increases synaptic strength and that activity-dependent synaptic upscaling occludes the subsequent RA-induced increase in synaptic strength. In addition, knocking down RARα expression in neurons using shRNA blocked both RA-induced and activity blockade-induced synaptic scaling. Direct activation of RARα with a selective agonist mimics the effect of RA, indicating the essential involvement of RARα in homeostatic plasticity. In our experiments, the synaptic effect of RA is independent of the formation of new dendritic spines, but instead operates by stimulating the synthesis and insertion of new postsynaptic glutamate receptors in existing synapses. Our results thus suggest that RA functions as a synaptic signal that operates via RARα during homeostatic plasticity to upregulate synaptic strength by increasing the size of the postsynaptic glutamate receptor response. We examined synaptic transmission in hippocampal pyramidal neurons from 5–7 day in vitro (DIV) cultured slices. Two hours after the addition of RA (1 μM) to the culture media, a significant increase in miniature excitatory postsynaptic current (mEPSC) amplitude was observed in comparison to DMSO-treated neurons (Figures 1A and 1B). The mEPSC frequency was not changed by RA treatment. The rapid time course of the RA effect on synaptic transmission was somewhat surprising, raising the question whether we could observe a similar phenomenon in dissociated cultured neurons. Indeed, a significant increase in mEPSC amplitude was induced in primary cultured hippocampal neurons as early as an hour after a 30 min treatment with RA (Figure 1C). Similar to the results from cultured slices, this RA-induced increase in synaptic transmission did not involve an increase in mEPSC frequency (Figures 1F), suggesting a postsynaptic mechanism. Analysis of the mEPSC amplitude distributions after DMSO or RA treatments showed that the RA-induced increase in synaptic strength was multiplicative, rather than additive (Figures 1D and 1E; compare green dots with dashed line in 1D), reminiscent of synaptic scaling induced by reduced network activity (Thiagarajan et al., 2005Thiagarajan T.C. Lindskog M. Tsien R.W. Adaptation to synaptic inactivity in hippocampal neurons.Neuron. 2005; 47: 725-737Abstract Full Text Full Text PDF PubMed Scopus (383) Google Scholar, Turrigiano et al., 1998Turrigiano G.G. Leslie K.R. Desai N.S. Rutherford L.C. Nelson S.B. Activity-dependent scaling of quantal amplitude in neocortical neurons.Nature. 1998; 391: 892-896Crossref PubMed Scopus (1529) Google Scholar). A recent report suggested that RA induces rapid spine formation by a mechanism that involves activation of the RA-receptor RARα exposed on the cell surface (Chen and Napoli, 2008Chen N. Napoli J.L. All-trans-retinoic acid stimulates translation and induces spine formation in hippocampal neurons through a membrane-associated RARalpha.FASEB J. 2008; 22: 236-245Crossref PubMed Scopus (124) Google Scholar). However, we observed no increase in spine density upon RA treatment (Figures 1G and S1), consistent with the lack of change in mEPSC frequency. Thus, at least under our conditions, RA causes a functional change in existing synapses without a major induction of new spines and synapses. Intrigued by the synaptic upscaling induced by RA, we next directly asked whether RA is involved in activity blockade-induced homeostatic synaptic plasticity. To test this question, we applied citral, an inhibitor of retinol dehydrogenase (ROLDH) (Di Renzo et al., 2007Di Renzo F. Broccia M.L. Giavini E. Menegola E. Citral, an inhibitor of retinoic acid synthesis, attenuates the frequency and severity of branchial arch abnormalities induced by triazole-derivative fluconazole in rat embryos cultured in vitro.Reprod. Toxicol. 2007; 24: 326-332Crossref PubMed Scopus (42) Google Scholar, Song et al., 2004Song Y. Hui J.N. Fu K.K. Richman J.M. Control of retinoic acid synthesis and FGF expression in the nasal pit is required to pattern the craniofacial skeleton.Dev. Biol. 2004; 276: 313-329Crossref PubMed Scopus (72) Google Scholar, Tanaka et al., 1996Tanaka M. Tamura K. Ide H. Citral, an inhibitor of retinoic acid synthesis, modifies chick limb development.Dev. Biol. 1996; 175: 239-247Crossref PubMed Scopus (34) Google Scholar), the enzyme that oxidizes all-trans retinol to all-trans retinal in the synthetic pathway of RA (Lane and Bailey, 2005Lane M.A. Bailey S.J. Role of retinoid signalling in the adult brain.Prog. Neurobiol. 2005; 75: 275-293Crossref PubMed Scopus (280) Google Scholar). Consistent with previous studies (Ju et al., 2004Ju W. Morishita W. Tsui J. Gaietta G. Deerinck T.J. Adams S.R. Garner C.C. Tsien R.Y. Ellisman M.H. Malenka R.C. Activity-dependent regulation of dendritic synthesis and trafficking of AMPA receptors.Nat. Neurosci. 2004; 7: 244-253Crossref PubMed Scopus (411) Google Scholar, Sutton et al., 2004Sutton M.A. Wall N.R. Aakalu G.N. Schuman E.M. Regulation of dendritic protein synthesis by miniature synaptic events.Science. 2004; 304: 1979-1983Crossref PubMed Scopus (198) Google Scholar, Sutton et al., 2006Sutton M.A. Ito H.T. Cressy P. Kempf C. Woo J.C. Schuman E.M. Miniature neurotransmission stabilizes synaptic function via tonic suppression of local dendritic protein synthesis.Cell. 2006; 125: 785-799Abstract Full Text Full Text PDF PubMed Scopus (455) Google Scholar), we found that blocking neuronal activity with TTX and APV for 24 hr induced a significant increase in mEPSC amplitude in cultured neurons (Figure 2A). This increase was blocked by addition of citral (Figure 2A). Moreover, we blocked RA synthesis with 4-(diethylamino)-benzaldehyde (DEAB), an inhibitor of retinal dehydrogenase (RALDH) (Russo et al., 1988Russo J.E. Hauguitz D. Hilton J. Inhibition of mouse cytosolic aldehyde dehydrogenase by 4-(diethylamino)benzaldehyde.Biochem. Pharmacol. 1988; 37: 1639-1642Crossref PubMed Scopus (71) Google Scholar), the enzyme that catalyzes the next step oxidation from ROLDH and converts all-trans retinal into RA. Similar to citral, DEAB completely blocked synaptic scaling induced by activity blockade (Figure 2B). These results suggest that RA synthesis is required for activity blockade-induced synaptic scaling. If activity blockade-induced synaptic scaling is mediated by RA signaling, it should occlude further scaling effects induced by direct RA treatment. In both hippocampal slice and primary cultures, the homeostatic increase in synaptic strength induced by blocking neuronal activity with TTX and APV for 24 hr, as manifested in a significant increase in mEPSC amplitude in pyramidal neurons, occludes the subsequent action of RA treatment (1 μM, 2 hr for slice cultures, 30 min for primary cultures) (Figures 2C and 2D). Taken together, these data strongly suggest that RA is critically involved in homeostatic synaptic plasticity. The intriguing possibility that activity blockade-induced synaptic scaling is mediated by RA signaling led us to examine whether RA synthesis can be regulated in an activity-dependent manner. Retinoids are stored intracellularly as retinyl ester, which are converted to retinol when needed. Retinol is then metabolized to RA (Lane and Bailey, 2005Lane M.A. Bailey S.J. Role of retinoid signalling in the adult brain.Prog. Neurobiol. 2005; 75: 275-293Crossref PubMed Scopus (280) Google Scholar). The oxidation that directly generates RA from retinal is catalyzed by retinal dehydrogenases (RALDHs) (Figure 3A). High levels of RALDH1 mRNA and protein are detected in fully differentiated hippocampal neurons, indicating that RA can be directly synthesized in neurons (Figures 3A and S2) (Wagner et al., 2002Wagner E. Luo T. Drager U.C. Retinoic acid synthesis in the postnatal mouse brain marks distinct developmental stages and functional systems.Cereb. Cortex. 2002; 12: 1244-1253Crossref PubMed Scopus (102) Google Scholar). To examine whether activity blockade enhances RA levels in neurons, we employed a retinoic acid response element (RARE)-based reporter system that has been widely used in vivo and in vitro to detect RA (Suzuki et al., 2006Suzuki T. Nishimaki-Mogami T. Kawai H. Kobayashi T. Shinozaki Y. Sato Y. Hashimoto T. Asakawa Y. Inoue K. Ohno Y. et al.Screening of novel nuclear receptor agonists by a convenient reporter gene assay system using green fluorescent protein derivatives.Phytomedicine. 2006; 13: 401-411Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar, Thompson Haskell et al., 2002Thompson Haskell G. Maynard T.M. Shatzmiller R.A. Lamantia A.S. Retinoic acid signaling at sites of plasticity in the mature central nervous system.J. Comp. Neurol. 2002; 452: 228-241Crossref PubMed Scopus (65) Google Scholar, Wagner et al., 1992Wagner M. Han B. Jessell T.M. Regional differences in retinoid release from embryonic neural tissue detected by an in vitro reporter assay.Development. 1992; 116: 55-66Crossref PubMed Google Scholar). We generated a reporter construct containing three copies of the DR5 variant of the retinoic acid response element (direct repeat with 5 bp of spacing) and a GFP reporter gene (3xDR5-RARE-GFP) to monitor RA production in cultured neurons (Figure 3B). The detection system was validated in HEK293 cells in which direct RA treatment induced a robust increase in GFP when transiently transfected with the 3xDR5-RARE-GFP reporter (Figures S3A and S3B). We transfected neurons at 13 DIV with 3xDR5-RARE-GFP and examined the GFP fluorescence intensity after 6 hr. Compared to the untreated condition, treatment with TTX and APV for 24 hr dramatically increased the expression of the GFP reporter, while a control GFP construct lacking the RARE regulatory sequence showed no change in expression (Figures 3C and 3D). Interestingly, blocking neuronal activity with TTX alone for 24 hr, a protocol that induces a mechanistically distinct form of synaptic scaling (Sutton et al., 2006Sutton M.A. Ito H.T. Cressy P. Kempf C. Woo J.C. Schuman E.M. Miniature neurotransmission stabilizes synaptic function via tonic suppression of local dendritic protein synthesis.Cell. 2006; 125: 785-799Abstract Full Text Full Text PDF PubMed Scopus (455) Google Scholar), did not yield a significant increase in the GFP reporter expression (Figures 3C and 3D). To further validate that the increased GFP reporter expression reflects synthesis of RA in neurons, we examined the effect of the RA synthesis blocker DEAB on reporter expression. DEAB, added to the neurons together with TTX and APV, reduced the GFP-reporter signal in a dose-dependent manner (Figures 3C and 3E). At a concentration of 10 μM, which blocked synaptic scaling induced by TTX + APV (Figure 2B), DEAB completely blocked RA synthesis, as indicated by a lack of significant increase in reporter expression (Figure 3E). It is worth noting that even with the highest DEAB concentration (100 μM), which presumably completely blocked RA synthesis, the GFP reporter expression levels were comparable to those found in mock-treated neurons, indicating that at basal conditions (no activity blockade), the ambient RA level in neurons is very low. To rule out the possibility that the observed increase in the GFP reporter expression was caused by activity-dependent changes in the neuron's general transcriptional and/or translational activity acting on the reporter and to directly test whether RA can act as a diffusible signal acting on neighboring cells (i.e., function in a cell-non-autonomous manner), we repeated the RA detection experiment using HEK293 cells transfected with the 3xDR5-RARE-GFP reporter. An hour after transfection, HEK293 cells were coplated with neurons. A significant increase in GFP expression in the HEK293 cells was observed as early as 8 hr after the onset of TTX and APV treatment in comparison to the mock-treated group, and the difference was retained 24 hr after onset of the activity blockade (Figures 3F and 3G). Treating HEK293 cells directly with TTX + APV for 24 hr did not affect 3xDR5-RARE-GFP reporter expression (Figure S4A). In addition, a control GFP construct lacking the RARE sequence did not show expression differences under these conditions (Figures 3G). Although the HEK293 cells plated directly on neurons were able to detect increased RA levels in TTX- and APV-treated neurons, conditioned media collected from neuronal cultures that had been treated with TTX and APV for 24 hr did not increase 3xDR5-RARE-GFP reporter expression in HEK293 cells (Figure S4B). The lack of free RA in the conditioned media was probably due to its lipophilic and labile nature. Taken together, these results demonstrate that blocking neuronal activity by the TTX and APV treatment strongly increases RA levels in neurons and that RA acts locally in these neurons and in surrounding cells. The selective increase of mEPSC amplitude but not frequency by RA treatment and the lack of an effect of RA on spine density suggest that RA acts postsynaptically to enhance synaptic strength in existing synapses. To examine whether RA increases synaptic transmission by increasing postsynaptic AMPA receptor function, we stained the cell surface of neurons treated with DMSO (vehicle) or 1 μM RA for surface-expressed GluR1 and GluR2 AMPA receptor subunits (Figures 4A). Indeed, RA significantly increased the surface levels of GluR1, but not of GluR2 (Figure 4B). We also examined surface GluR1 expression levels with surface protein biotinylation. Either RA or TTX + APV treatment alone significantly increased the surface GluR1 level (Figures 4C and 4D). However, application of both treatments together did not produce additional enhancement (Figures 4C and 4D), consistent with our electrophysiological results demonstrating that activity blockade-induced synaptic scaling occludes RA-induced increase in synaptic transmission (Figures 2C and 2D). The selective increase in GluR1 surface expression by RA suggests that homomeric GluR1 receptors are inserted during RA-induced synaptic scaling. Activity blockade-induced synaptic scaling is mediated by homomeric GluR1 receptors and can be blocked by philanthotoxin-433 (PhTx), a blocker of homomeric AMPA receptors lacking the GluR2 subunit (Ju et al., 2004Ju W. Morishita W. Tsui J. Gaietta G. Deerinck T.J. Adams S.R. Garner C.C. Tsien R.Y. Ellisman M.H. Malenka R.C. Activity-dependent regulation of dendritic synthesis and trafficking of AMPA receptors.Nat. Neurosci. 2004; 7: 244-253Crossref PubMed Scopus (411) Google Scholar, Shepherd et al., 2006Shepherd J.D. Rumbaugh G. Wu J. Chowdhury S. Plath N. Kuhl D. Huganir R.L. Worley P.F. Arc/Arg3.1 mediates homeostatic synaptic scaling of AMPA receptors.Neuron. 2006; 52: 475-484Abstract Full Text Full Text PDF PubMed Scopus (535) Google Scholar, Sutton et al., 2006Sutton M.A. Ito H.T. Cressy P. Kempf C. Woo J.C. Schuman E.M. Miniature neurotransmission stabilizes synaptic function via tonic suppression of local dendritic protein synthesis.Cell. 2006; 125: 785-799Abstract Full Text Full Text PDF PubMed Scopus (455) Google Scholar, Thiagarajan et al., 2005Thiagarajan T.C. Lindskog M. Tsien R.W. Adaptation to synaptic inactivity in hippocampal neurons.Neuron. 2005; 47: 725-737Abstract Full Text Full Text PDF PubMed Scopus (383) Google Scholar). Indeed, the RA-induced increase in mEPSC amplitude was reversed by bath application of 5 μM PhTx in dissociated cultures (Figures 4E and 4F) and in hippocampal slice cultures (Figure 4G), indicating that RA-induced synaptic insertion of homomeric GluR1 receptors is responsible for the observed scaling effect. In contrast, basal synaptic transmission was not affected by PhTx (Figure S5), which is consistent with the notion that AMPA receptors supporting basal synaptic transmission are GluR2-containing heteromeric receptors. Activity blockade-induced, in particular, TTX- and APV-induced, synaptic scaling requires dendritic protein translation (Ju et al., 2004Ju W. Morishita W. Tsui J. Gaietta G. Deerinck T.J. Adams S.R. Garner C.C. Tsien R.Y. Ellisman M.H. Malenka R.C. Activity-dependent regulation of dendritic synthesis and trafficking of AMPA receptors.Nat. Neurosci. 2004; 7: 244-253Crossref PubMed Scopus (411) Google Scholar, Sutton et al., 2004Sutton M.A. Wall N.R. Aakalu G.N. Schuman E.M. Regulation of dendritic protein synthesis by miniature synaptic events.Science. 2004; 304: 1979-1983Crossref PubMed Scopus (198) Google Scholar, Sutton et al., 2006Sutton M.A. Ito H.T. Cressy P. Kempf C. Woo J.C. Schuman E.M. Miniature neurotransmission stabilizes synaptic function via tonic suppression of local dendritic protein synthesis.Cell. 2006; 125: 785-799Abstract Full Text Full Text PDF PubMed Scopus (455) Google Scholar). GluR1 mRNA is found in neuronal dendrites, and is believed to be translated locally (Grooms et al., 2006Grooms S.Y. Noh K.M. Regis R. Bassell G.J. Bryan M.K. Carroll R.C. Zukin R.S. Activity bidirectionally regulates AMPA receptor mRNA abundance in dendrites of hippocampal neurons.J. Neurosci. 2006; 26: 8339-8351Crossref PubMed Scopus (135) Google Scholar, Miyashiro et al., 1994Miyashiro K. Dichter M. Eberwine J. On the nature and differential distribution of mRNAs in hippocampal neurites: implications for neuronal functioning.Proc. Natl. Acad. Sci. USA. 1994; 91: 10800-10804Crossref PubMed Scopus (235) Google Scholar, Poon et al., 2006Poon M.M. Choi S.H. Jamieson C.A. Geschwind D.H. Martin K.C. Identification of process-localized mRNAs from cultured rodent hippocampal neurons.J. Neurosci. 2006; 26: 13390-13399Crossref PubMed Scopus (160) Google Scholar). To test whether RA induces an increase in postsynaptic GluR1, we investigated whether RA-induced synaptic scaling depends on gene transcription or translation. The protein synthesis inhibitor anisomycin (40 μM) blocked the RA-induced increase in mEPSC amplitude in both hippocampal slice cultures (Figure 5A) and dissociated cultures (Figures 5B). Moreover, the increase in surface GluR1 expression by RA treatment was also completely prevented by anisomycin or cycloheximide (100 μM; see Figure 5C). By contrast, the transcription inhibitor actinomycin D (50 μM) failed to block the effects of RA on mEPSC amplitude or on surface GluR1 expression (Figures 5A–5C). Thus, RA regulates synaptic transmission by a translation-dependent but transcription-independent mechanism. Combining in situ hybridization and immunocytochemistry, we found that GluR1 mRNA was present in neuronal dendrites (Figure 6A), consistent with previous reports (Grooms et al., 2006Grooms S.Y. Noh K.M. Regis R. Bassell G.J. Bryan M.K. Carroll R.C. Zukin R.S. Activity bidirectionally regulates AMPA receptor mRNA abundan" @default.
• W2050519369 created "2016-06-24" @default.
• W2050519369 creator A5003413224 @default.
• W2050519369 creator A5037917072 @default.
• W2050519369 creator A5044835859 @default.
• W2050519369 creator A5066064232 @default.
• W2050519369 creator A5088634670 @default.
• W2050519369 date "2008-10-01" @default.
• W2050519369 modified "2023-10-12" @default.
• W2050519369 title "Synaptic Signaling by All-Trans Retinoic Acid in Homeostatic Synaptic Plasticity" @default.
• W2050519369 cites W132800290 @default.
• W2050519369 cites W1514853588 @default.
• W2050519369 cites W1542136448 @default.
• W2050519369 cites W1548862642 @default.
• W2050519369 cites W1869370853 @default.
• W2050519369 cites W1965265446 @default.
• W2050519369 cites W1965960354 @default.
• W2050519369 cites W1968164494 @default.
• W2050519369 cites W1976405146 @default.
• W2050519369 cites W1985362922 @default.
• W2050519369 cites W1990264946 @default.
• W2050519369 cites W1991452746 @default.
• W2050519369 cites W1994307860 @default.
• W2050519369 cites W1997815735 @default.
• W2050519369 cites W1998254077 @default.
• W2050519369 cites W1999170657 @default.
• W2050519369 cites W1999935629 @default.
• W2050519369 cites W2002295532 @default.
• W2050519369 cites W2004803686 @default.
• W2050519369 cites W2013185658 @default.
• W2050519369 cites W2015701831 @default.
• W2050519369 cites W2016032579 @default.
• W2050519369 cites W2017964520 @default.
• W2050519369 cites W2019808076 @default.
• W2050519369 cites W2021235911 @default.
• W2050519369 cites W2024822097 @default.
• W2050519369 cites W2027575557 @default.
• W2050519369 cites W2027699509 @default.
• W2050519369 cites W2030827475 @default.
• W2050519369 cites W2031779883 @default.
• W2050519369 cites W2031898618 @default.
• W2050519369 cites W2038841625 @default.
• W2050519369 cites W2044643509 @default.
• W2050519369 cites W2047419060 @default.
• W2050519369 cites W2047673461 @default.
• W2050519369 cites W2048358400 @default.
• W2050519369 cites W2051663421 @default.
• W2050519369 cites W2058812571 @default.
• W2050519369 cites W2062022610 @default.
• W2050519369 cites W2064438779 @default.
• W2050519369 cites W2069705491 @default.
• W2050519369 cites W2069863147 @default.
• W2050519369 cites W2070635928 @default.
• W2050519369 cites W2077139708 @default.
• W2050519369 cites W2083796374 @default.
• W2050519369 cites W2090887381 @default.
• W2050519369 cites W2093725075 @default.
• W2050519369 cites W2102611655 @default.
• W2050519369 cites W2103178300 @default.
• W2050519369 cites W2104580322 @default.
• W2050519369 cites W2111504220 @default.
• W2050519369 cites W2114559471 @default.
• W2050519369 cites W2120657236 @default.
• W2050519369 cites W2122827236 @default.
• W2050519369 cites W2125161058 @default.
• W2050519369 cites W2125577585 @default.
• W2050519369 cites W2129626119 @default.
• W2050519369 cites W2133141667 @default.
• W2050519369 cites W2133312355 @default.
• W2050519369 cites W2141851583 @default.
• W2050519369 cites W2148271975 @default.
• W2050519369 cites W2254919660 @default.
• W2050519369 doi "https://doi.org/10.1016/j.neuron.2008.08.012" @default.
• W2050519369 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/2634746" @default.
• W2050519369 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/18957222" @default.
• W2050519369 hasPublicationYear "2008" @default.
• W2050519369 type Work @default.
• W2050519369 sameAs 2050519369 @default.
• W2050519369 citedByCount "327" @default.
• W2050519369 countsByYear W20505193692012 @default.
• W2050519369 countsByYear W20505193692013 @default.
• W2050519369 countsByYear W20505193692014 @default.
• W2050519369 countsByYear W20505193692015 @default.
• W2050519369 countsByYear W20505193692016 @default.
• W2050519369 countsByYear W20505193692017 @default.
• W2050519369 countsByYear W20505193692018 @default.
• W2050519369 countsByYear W20505193692019 @default.
• W2050519369 countsByYear W20505193692020 @default.
• W2050519369 countsByYear W20505193692021 @default.
• W2050519369 countsByYear W20505193692022 @default.
• W2050519369 countsByYear W20505193692023 @default.
• W2050519369 crossrefType "journal-article" @default.
• W2050519369 hasAuthorship W2050519369A5003413224 @default.
• W2050519369 hasAuthorship W2050519369A5037917072 @default.
• W2050519369 hasAuthorship W2050519369A5044835859 @default.
• W2050519369 hasAuthorship W2050519369A5066064232 @default.
• W2050519369 hasAuthorship W2050519369A5088634670 @default.
• W2050519369 hasBestOaLocation W20505193691 @default.

• next