Cited by 83Tuberous Sclerosis Complex ResearchGenetics and Neurodevelopmental DisordersNeuroscience and Neuropharmacology Research

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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Chévere-Torres, Itzamarie, Kaphzan, Hanoch, Bhattacharya, Aditi, Kang, Areum, Maki, Jordan M., Gambello, Michael J., Arbiser, Jack L., Santini, Emanuela +1 more·2012·Neurobiology of Disease

Abstract

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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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
Venue
Neurobiology of Disease
Publisher
Elsevier BV
Published
2012-03
Volume
45
Issue
3
Pages
1101-1110
ISSN
0969-9961 (ISSN-L)
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
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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