Metabotropic glutamate receptor-dependent long-term depression is impaired due to elevated ERK signaling in the ΔRG mouse model of tuberous sclerosis complex
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Tuberous sclerosis complex (TSC) and fragile X syndrome (FXS) are caused by mutations in negative regulators of translation. FXS model mice exhibit enhanced metabotropic glutamate receptor-dependent long-term depression (mGluR-LTD). Therefore, we hypothesized that a mouse model of TSC, ΔRG transgenic mice, also would exhibit enhanced mGluR-LTD. We measured the impact of TSC2-GAP mutations on the mTORC1 and ERK signaling pathways and protein synthesis-dependent hippocampal synaptic plasticity in ΔRG transgenic mice. These mice express a dominant/negative TSC2 that binds to TSC1, but has a deletion and substitution mutation in its GAP-domain, resulting in inactivation of the complex. Consistent with previous studies of several other lines of TSC model mice, we observed elevated S6 phosphorylation in the brains of ΔRG mice, suggesting upregulated translation. Surprisingly, mGluR-LTD was not enhanced, but rather was impaired in the ΔRG transgenic mice, indicating that TSC and FXS have divergent synaptic plasticity phenotypes. Similar to patients with TSC, the ΔRG transgenic mice exhibit elevated ERK signaling. Moreover, the mGluR-LTD impairment displayed by the ΔRG transgenic mice was rescued with the MEK-ERK inhibitor U0126. Our results suggest that the mGluR-LTD impairment observed in ΔRG mice involves aberrant TSC1/2-ERK signaling.
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LTD is attenuated in Tsc2+/- mice and in the Tsc2ΔRG loss-of-function mutant.
“Furthermore, LTD is attenuated, both in Tsc2+/- (Auerbach et al., 2011; Bateup et al., 2011), and in a loss of function mutant, Tsc2ΔRG, that weakens translational braking (Chevere-Torres et al., 2012).”
From Unifying Views of Autism Spectrum Disorders: A Consideration of Autoregulatory Feedback Loops (2016) · cites this paper as Chevere-Torres et al., 2012
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Self-citation
- Authors
- Chévere-Torres, I., Kaphzan, H., Bhattacharya, A., Kang, A., Maki, J. M., Gambello, M. J., Arbiser, J. L., Santini, E., & Klann, E.
- Affiliations
- New York University (US)
- The University of Texas Health Science Center at Houston (US)
- Emory University (US)
- Corresponding author
- Klann, Eric
- ORCID
- Venue
- Neurobiology of Disease
- Publisher
- Elsevier BV
- Published
- 2012-03
- Volume
- 45
- Issue
- 3
- Pages
- 1101-1110
- ISSN
- 0969-9961 (ISSN-L)
- PMC
- PMC3276695
- OpenAlex
- W1976753789
- Cited by
- 83
- References
- 56
- Citations by year
- 2026: 4 · 2025: 1 · 2024: 3 · 2023: 3 · 2022: 6 · 2021: 4 · 2020: 9 · 2019: 3 · 2018: 4 · 2017: 7 · 2016: 8 · 2015: 9 · 2014: 8 · 2013: 8 · 2012: 5
- FWCI
- 4.58
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Neurobiology of Disease (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institutes of Health (NS034007, NS047384, MH085489)
- Topics
- Health Sciences › Medicine › Physiology › Tuberous Sclerosis Complex Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- tuberous sclerosis complex, metabotropic glutamate receptors, long-term depression, ERK signaling, TSC1, mTORC1, S6 phosphorylation, protein synthesis, synaptic plasticity, fragile X syndrome, U0126, MEK/ERK inhibition, hippocampus
- MeSH terms
- Tuberous Sclerosis Complex 1 Protein, Tuberous Sclerosis Complex 2 Protein, Analysis of Variance, Animals, Animals, Newborn, Biophysics, Disease Models, Animal, Dose-Response Relationship, Drug, Electric Stimulation, Enzyme Inhibitors, Hippocampus, Methoxyhydroxyphenylglycol, Mice, Inbred C57BL, Mice, Transgenic, Tuberous Sclerosis, Receptors, Metabotropic Glutamate, Patch-Clamp Techniques, Excitatory Amino Acid Agents, Ribosomal Protein S6 Kinases, GTPase-Activating Proteins, MAP Kinase Signaling System, Tumor Suppressor Proteins, Long-Term Synaptic Depression, Mice, Calcium-Calmodulin-Dependent Protein Kinase Type 2, In Vitro Techniques
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