Activation of the phosphoinositide 3-kinase-Akt-mammalian target of rapamycin signaling pathway is required for metabotropic glutamate receptor-dependent long-term depression
Open accessAbstract
Hippocampal long-term depression (LTD) is a long-lasting decrease in synaptic strength that is most commonly studied at glutamatergic inputs to pyramidal cells in hippocampal area CA1. Activation of G-protein-coupled group I (including types 1 and 5) metabotropic glutamate receptors (mGluRs) by the pharmacological agonist ( RS )-3,5-dihydroxyphenylglycine (DHPG) elicits LTD in area CA1 of the hippocampus. Recent reports have shown that de novo protein synthesis is necessary for DHPG-induced LTD. However, relatively little is known about the signaling pathways that couple mGluRs to translation initiation. In this study, we investigated whether the activation of the phosphoinositide 3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) pathway, which has been shown to regulate translation initiation, is necessary for mGluR-LTD induced by DHPG. We found that brief incubations of mouse hippocampal slices with DHPG resulted in increased phosphorylation of Akt and mTOR in hippocampal area CA1. Two structurally unrelated PI3K inhibitors, LY294002 and wortmannin, blocked the DHPG-induced increases in phosphorylation of Akt and mTOR. Biochemical fractionation studies showed that the DHPG-induced increase in the phosphorylation of Akt and mTOR could be detected in synaptoneurosome preparations, and immunohistochemical analysis revealed that similar increases could be detected in both stratum pyramidale and stratum radiatum in area CA1. Finally, we observed that both PI3K inhibitors and rapamycin, an mTOR inhibitor, prevented mGluR-LTD induced by DHPG. Together, our findings indicate that activation of the PI3K-Akt-mTOR signaling cascade is required for mGluR-LTD and suggest that this pathway may couple group I mGluRs to translation initiation in hippocampal area CA1.
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mTORC1 tightly coordinates LTP and LTD, the molecular correlates of learning and memory.
“In the brain, mTORC1 tightly coordinates different synaptic plasticities -long-term potentiation (LTP) and long-term depression (LTD) -the molecular correlates of learning and memory (2)(3)(4)(5).”
From Analysis of proteins that rapidly change upon mechanistic/mammalian target of rapamycin complex 1 (mTORC1) repression identifies parkinson protein 7 (PARK7) as a novel protein aberrantly expressed in tuberous sclerosis complex (TSC) (2016) · cites this paper as [3]
The section “mTOR is required for protein synthesis-dependent forms of synaptic plasticity” reports that certain forms of LTP require mTOR and that this study found mTOR necessary for mGluR-LTD. The Introduction describes hippocampal LTD as a possible substrate for learning and memory. The paper does not specifically identify mTORC1 or establish that it tightly coordinates LTP and LTD generally. Page numbers were unavailable in our copy. (LLM, conf=0.85)
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- Authors
- Hou, L., & Klann, E.
- Affiliations
- Baylor College of Medicine (US)
- ORCID
- Klann, Eric
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2004-07-14
- Volume
- 24
- Issue
- 28
- Pages
- 6352-6361
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6729543
- OpenAlex
- W2143034003
- Cited by
- 527
- References
- 3
- Citations by year
- 2026: 11 · 2025: 10 · 2024: 17 · 2023: 14 · 2022: 19 · 2021: 18 · 2020: 30 · 2019: 14 · 2018: 26 · 2017: 22 · 2016: 33 · 2015: 30 · 2014: 34 · 2013: 35 · 2012: 42
- FWCI
- 8.34
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- FRAXA Research Foundation
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke (R37NS034007, NS-34007, R01NS034007, R29NS034007)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Keywords
- metabotropic glutamate receptors, group I mGluRs, long-term depression, PI3K/AKT/mTOR pathway, DHPG, translation initiation, de novo protein synthesis, hippocampal CA1, Akt phosphorylation, mTOR phosphorylation, PI3K inhibitors, rapamycin, synaptic plasticity
- MeSH terms
- Wortmannin, Phosphoinositide-3 Kinase Inhibitors, Androstadienes, Animals, Benzoates, Chromones, Dendrites, Enzyme Inhibitors, Glycine, Hippocampus, Male, Mice, Inbred C57BL, Morpholines, Phosphorylation, Protein Kinases, Protein Processing, Post-Translational, Proto-Oncogene Proteins, Pyridines, Resorcinols, Synaptosomes, Signal Transduction, Tacrolimus, Protein Serine-Threonine Kinases, Pyramidal Cells, Receptors, Metabotropic Glutamate, Excitatory Amino Acid Agonists, Phosphatidylinositol 3-Kinases, Sirolimus, Long-Term Synaptic Depression, Proto-Oncogene Proteins c-akt, Mice, TOR Serine-Threonine Kinases, 3-Phosphoinositide-Dependent Protein Kinases, Receptor, Metabotropic Glutamate 5
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