Roles of Glutamate Receptors and the Mammalian Target of Rapamycin (mTOR) Signaling Pathway in Activity-dependent Dendritic Protein Synthesis in Hippocampal Neurons
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Local protein synthesis in neuronal dendrites is critical for synaptic plasticity. However, the signaling cascades that couple synaptic activation to dendritic protein synthesis remain elusive. The purpose of this study is to determine the role of glutamate receptors and the mammalian target of rapamycin (mTOR) signaling in regulating dendritic protein synthesis in live neurons. We first characterized the involvement of various subtypes of glutamate receptors and the mTOR kinase in regulating dendritic synthesis of a green fluorescent protein (GFP) reporter controlled by alphaCaMKII 5' and 3' untranslated regions in cultured hippocampal neurons. Specific antagonists of N-methyl-d-aspartic acid (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and metabotropic glutamate receptors abolished glutamate-induced dendritic GFP synthesis, whereas agonists of NMDA and metabotropic but not AMPA glutamate receptors activated GFP synthesis in dendrites. Inhibitions of the mTOR signaling, as well as its upstream activators, phosphatidylinositol 3-kinase and AKT, blocked NMDA receptor-dependent dendritic GFP synthesis. Conversely, activation of mTOR signaling stimulated dendritic GFP synthesis. In addition, we also found that inhibition of the mTOR kinase blocked dendritic synthesis of the endogenous alphaCaMKII and MAP2 proteins induced by tetanic stimulations in hippocampal slices. These results identify critical roles of NMDA receptors and the mTOR signaling pathway for control of synaptic activity-induced dendritic protein synthesis in hippocampal neurons.
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Activation of mTOR has been functionally linked with local protein synthesis of presynaptic synapsin I (SYN1) and cytoskeletal proteins such as ARC.
“Activation of mTOR has been functionally linked with local protein synthesis, such as the presynaptically as synapsin I (SYN1), as well as cytoskeletal proteins, such as the activity-regulated cytoskeletal-associated protein (ARC) [15,24,25].”
From The Impact of BDNF, NTRK2, NGFR, CREB1, GSK3B, AKT, MAPK1, MTOR, PTEN, ARC, and SYN1 Genetic Polymorphisms in Antidepressant Treatment Response Phenotypes (2023) · cites this paper as [25]
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“BDNF modulates dendritic growth and plasticity by activating PI3K/mTOR signaling downstream of binding to the tyrosine kinase (Trk) receptors, which are members of the RTK family of transmembrane receptors (Gong et al., 2006; Jaworski et al., 2005; Kumar et al., 2005; Takei et al., 2004).”
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“Additional mRNAs that are translated in response to mTORC1 activation have well characterized roles in synaptic function and plasticity, and include NR1, CamKII alpha, PSD95, Arc, and PKM zeta (Gong et al., 2006; Kelly et al., 2007; Lee et al., 2005; Schratt et al., 2004).”
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“, 2002), where its activation is controlled by a variety of extracellular stimuli, including glutamate (Cammalleri et al., 2003; Hou and Klann, 2004; Gong et al., 2006) and brain-derived neurotrophic factor (BDNF) (Takei et al.”
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“2006), possibly mediated by an mTOR-dependent increase in local dendritic synthesis of AMPA receptors (Gong et al. 2006).”
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“There is also evidence that mTOR modulates activitydependent synaptic plasticity in the dendrites of hippocampal neurons (Gong et al., 2006), although the specific role of autophagy was not investigated.”
BackgroundOn the participation of mTOR in recognition memory.
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“mTORC1 activation can result in translation of additional mRNAs, which have specific roles in synaptic function and plasticity, including NR1, CamKIIalpha, PSD95, Arc, and PKM zeta [18,20,21].”
BackgroundmTOR complex 1: a key player in neuroadaptations induced by drugs of abuse
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“…signaling Several studies have shown that mTORC1 signaling can be triggered in response to activation of the NMDA receptor (Cammalleri et al. 2003; Gong et al. 2006) whose activity is an important mediator of cocaine and alcohol-dependent behaviors (Wang et al. 2007, 2010a; Stuber et al. 2010).”
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“Several studies have shown that mTOR signaling is critical for activity-dependent synaptic plasticity in a variety of systems (Casadio et al., 1999; Tang et al., 2002; Gong et al., 2006).”
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“Thus, both translation regulators ERK1/2 and mTOR are phosphorylated after Group I mGluR activation in striatum and cortex (Choe and Wang, 2001a; Gong et al., 2006; Volk et al., 2006; Antion et al., 2008), and CaMKII also activates these regulators (Vanhoutte et al., 1999), although the role of…”
BackgroundInfluentialAlterations in Mammalian Target of Rapamycin Signaling Pathways after Traumatic Brain Injury
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“Brief glutamatergic stimulation of cultured neurons activates mTOR to an extent approaching that elicited by brain-derived neurotrophic factor (Gong et al, 2006).”
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Fluoxetine regulates mTOR signalling in a region-dependent manner in depression-like mice
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“Interestingly, recent work has shown that neuronal activity triggers rapid mRNA translation via an mTOR-dependent mechanism (Gong et al., 2006; Gelinas et al., 2007; Tsokas et al., 2007; Di Nardo et al.,2007) and that disruption of mTORC1 inhibits late phase longterm potentiation (LTP) in the…”
BackgroundPilar-Cuéllar, F., Vidal, R., Díaz, Á., Castro, E., dos Anjos, S., Pascual-Brazo, J., Linge, R., Vargas, V., Blanco, H., Martínez-Villayandre, B., et al. (2013) · Journal of Neural Transplantation and Plasticity · doi:10.1155/2013/537265 · Cited by 93 · see citing works
“…synapsin I, or postsynaptically as PSD-95 and GluR1, and cytoskeletal proteins as the activity-regulated cytoskeletal-associated protein (Arc) [27, 241, 243]. mTOR-signaling pathway has been also related to a number of neurological diseases, such as Alzheimer’s disease, Parkinson’s disease, and…”
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“Previous studies have revealed that mTOR signaling is a major molecular pathway in the control of activity-regulated protein synthesis during synaptic plasticity [33-35].”
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“Translational expression from this reporter has been shown to be induced by activity and is normally weak in dendrites distal to the cell body in unstimulated conditions (Aakalu et al., 2001; Gong et al., 2006).”
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“This last action is, at least partly, achieved by regulating the synthesis of the N-MethylD-Aspartate (NMDA) receptor subunit 1 (NR1) [33], calcium calmodulin-dependent kinase II α (CaMKIIα) [34] and postsynaptic density-95 (PSD-95) [35].”
BackgroundMacromolecular synthesis, distributed synaptic plasticity, and fear conditioning.
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“control the synthesis of locally translated proteins at active synapses (Cammalleri, et al., 2003; Gong et al., 2006; Tang, et al., 2002).”
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“Cyclin-dependent kinase 5, a proline-directed serine/threonine kinase can also phosphorylate the Homer binding domain of both mGluR1 and mGluR5, enhancing the interaction (Orlando et al., 2009).”
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Consolidation and translation regulationPreprint
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“Distinct types of glutamate receptors, such as NMDAR, AMPAR, and mGluRs are required for activation of mTOR/S6K signaling and CaMK__a synthesis in hippocampal dendrites following LTP (Cammalleri et al. 2003; Gong et al. 2006).”
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“Gong et al. (2006), in their experiments with mouse embryonic neurons, showed that rapamycin inhibited hippo-”
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“C57BL E18 cortical cultures were prepared, as described”
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“Akt1-mTOR signaling is a key component of activitydependent local dendritic protein translation (15, 44, 48).”
Therapeutic role of mammalian target of rapamycin (mTOR) inhibition in preventing epileptogenesis
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“Since putative learning mechanisms, such as long term potentiation and long term depression, rely on protein synthesis for sustained changes in synaptic strength, it is not surprising that they require mTOR activity [40, 50, 102].”
BackgroundTaking aim at Alzheimer’s disease through the mammalian target of rapamycin
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“Dendritic protein synthesis in hippocampal neurons is promoted through mTOR activity (Gong et al., 2006).”
BackgroundControl of synaptic plasticity and memory via suppression of poly(A)-binding protein.
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“The procedures for fluorescent immunostaining and data analysis were previously described (Gong et al., 2006).”
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“…these studies suggest that glutamate receptor activation may interact with the mTOR pathway, with other studies suggesting transcriptional and translational changes at the synapse that could mediate the molecular mechanics of these changes (Gong et al., 2006; Talos et al., 2012; Sun et al., 2013).”
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Retrograde changes in presynaptic function driven by dendritic mTORC1
Henry, F. E., McCartney, A. J., Neely, R., Perez, A. S., Carruthers, C., Stuenkel, E., Inoki, K., & Sutton, M. A. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.2149-12.2012 · Cited by 68 · see citing works
“…an important control point for protein synthesis related to synaptic plasticity (Casadio et al., 1999; Tang et al., 2002; Cammalleri et al., 2003; Gong et al., 2006) and memory (Tischmeyer et al., 2003; Dash et al., 2006; Blundell et al., 2008). mTOR is a serine/threonine protein kinase that…”
BackgroundCurrent Management of Tuberous Sclerosis Complex
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“This discrepancy is probably due to NMDAstimulated rapid translation from pre-existing mRNA, as suggested by previous studies (Ouyang et al., 1999; Gong et al., 2006; Li et al., 2012).”
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“Neuronal activity regulates the mTOR pathway (Lenz and Avruch, 2005; Gong et al., 2006; Raab-Graham et al., 2006), but molecular mechanisms for these influences have not been readily evident.”
Downregulated AKT-mTOR signaling pathway proteins in dorsolateral prefrontal cortex in Schizophrenia
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“, 2007), and specifically a critical role in control of synaptic activity-induced protein synthesis (such as -CaMKII and MAP2) in hippocampal neurons (Gong et al., 2006).”
BackgroundWang, H.-K., Huang, B.-Y., Wang, W., Li, J.-F., Chen, Y., Flynn, T., Zhao, M., Zhou, Z., Lin, X.-J., Zhang, Y.-N., et al. (2019) · EBioMedicine · doi:10.1016/j.ebiom.2019.09.049 · Cited by 61 · see citing works
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“…enhancement, in turn, resulted in a selective activation of the Akt-dependent pathway that subsequently activated both mTOR and S6 phosphorylation (Gong et al., 2006), a canonical pathway known to be activated by (a) 150 * * * *** * * Homogenate Crude synaptosomal fraction tr kB p ro te in le…”
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“Primary cultures of cortical neurons were prepared from C57BL/6 mouse embryos (E16) as previously described (40, 41).”
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“…is a member of serine/threonine protein kinase and plays an essential role in cell growth and survival through its regulation on initiation of translation (Guertin and Sabatini 2005). mTOR function is regulated by the activation of glutamate N-methyl-D-aspartate (NMDA) receptors (Gong et al. 2006).”
Therapeutic promise and principles: Metabotropic glutamate receptors
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“mTOR can directly act at synapses to promote synthesis of proteins necessary to facilitate plasticity, including NR1, CaMKIIa, PSD-95, Arc, and protein kinase C isoform protein kinase M zeta (Lee et al. 2005; Gong et al. 2006; Kelly et al. 2007; Garelick and Kennedy 2011).”
BackgroundmTORC1-dependent protein synthesis underlying rapid antidepressant effect requires GABABR signaling.
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“Because activation of mTOR kinase is generally regarded as a consequence of NMDAR stimulation, it is unknown how NMDAR antagonists increase active mTOR (Gong et al., 2006; Raab-Graham et al., 2006).”
BackgroundDendritic mRNA targeting and translation.
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“Since mTOR plays important roles in regulating dendritic protein synthesis, synapse formation, synaptic plasticity, and learning and memory (Cammalleri et al., 2003; Kelleher et al., 2004; Takei et al., 2004; Gong et al., 2006; Parsons et al., 2006; Slipczuk et al., 2009), the observed loss of dendritic spines could p…”
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“Dendrite protein synthesis is particularly dependent on group I mGluRs activation in the hippocampus (Gong et al., 2006).”
BackgroundInhibition of the mTOR pathway by rapamycin blocks cocaine-induced locomotor sensitization
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“Furthermore, mTOR activity has been noted to promote the synthesis of dendritic proteins within hippocampal neurons [45].”
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Fragile x mental retardation (Fmr-1) gene expression is down regulated in brain of mice during aging
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Striking a balance: PIP2 and PIP3 signaling in neuronal health and disease
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“The stimulation of mTOR increases dendritic protein synthesis locally and contributes to synaptic and structural plasticity [150, 151].”
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“…of mTOR) (Blundell et al. 2008; Parsons et al. 2006). mTOR is an important neuronal regulatory protein, capable of phosphorylating multiple downstream target proteins to inhibit cell death processes associated with cognitive impairment (Goncalves et al. 2017; Gong et al. 2006; Zare et al. 2013).”
BackgroundDendritic protein synthesis in the normal and diseased brain
Swanger, S., & Bassell, G. (2012) · Neuroscience · doi:10.1016/j.neuroscience.2012.12.003 · Cited by 46 · see citing works
“studies showed that activation of NMDA, mGlu1/5, and estrogen receptors also induce local GFP synthesis using 30 UTR reporters (Gong et al., 2006; Sarkar et al., 2010).”
BackgroundMethodInfluentialMedalla, M., Chang, W., Calderazzo, S. M., Go, V., Tsolias, A., Goodliffe, J., Pathak, D., Alba, D. D., Pessina, M. A., Rosene, D., et al. (2020) · Journal of Neuroscience · doi:10.1523/jneurosci.2226-19.2020 · Cited by 45 · see citing works
“In rodents, mTOR activation in vivo promotes hyperexcitability, axonal sprouting, and synthesis of MAP2 in dendrites (Gong et al., 2006; Park et al., 2008; Lee et al., 2014), whereas mTOR inhibition can increase dendritic K1 and NMDA channel expression (Raab-Graham et al., 2006).”
Background
- Authors
- Gong, R., Park, C. S., Abbassi, N. R., & Tang, S.-J.
- Affiliations
- University of California, Irvine (US)
- Corresponding author
- Tang, Shao-Jun
- ORCID
- Tang, Shao-Jun
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2006-07
- Volume
- 281
- Issue
- 27
- Pages
- 18802-18815
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2064438779
- Cited by
- 249
- References
- 73
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 6 · 2023: 6 · 2022: 11 · 2021: 14 · 2020: 11 · 2019: 7 · 2018: 13 · 2017: 14 · 2016: 10 · 2015: 21 · 2014: 14 · 2013: 19 · 2012: 25
- FWCI
- 6.33
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- dendritic protein synthesis, glutamate receptors, mTOR signaling, NMDA receptor, AMPA receptors, metabotropic glutamate receptors, hippocampal neurons, synaptic plasticity, CaMKIIα, MAP2, phosphatidylinositol 3-kinase, Akt, tetanic stimulation, local translation
- MeSH terms
- Animals, Cells, Cultured, Dendrites, Hippocampus, Neurons, Protein Kinases, Synapses, Signal Transduction, Receptors, N-Methyl-D-Aspartate, Receptors, Glutamate, Calcium-Calmodulin-Dependent Protein Kinases, Genes, Reporter, Green Fluorescent Proteins, Mice, Calcium-Calmodulin-Dependent Protein Kinase Type 2, TOR Serine-Threonine Kinases
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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