Cited by 84Genetics and Neurodevelopmental DisordersRNA and protein synthesis mechanismsPI3K/AKT/mTOR signaling in cancer

Elevated ERK/p90 ribosomal S6 kinase activity underlies audiogenic seizure susceptibility in fragile X mice

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Sawicka, Kirsty, Pyronneau, Alexander, Chao, Miranda, Bennett, Michael V. L., Zukin, R. Suzanne·2016·Proceedings of the National Academy of Sciences

Abstract

Fragile X syndrome (FXS) is the most common heritable cause of intellectual disability and a leading genetic form of autism. The Fmr1 KO mouse, a model of FXS, exhibits elevated translation in the hippocampus and the cortex. ERK (extracellular signal-regulated kinase) and mTOR (mechanistic target of rapamycin) signaling regulate protein synthesis by activating downstream targets critical to translation initiation and elongation and are known to contribute to hippocampal defects in fragile X. Here we show that the effect of loss of fragile X mental retardation protein (FMRP) on these pathways is brain region specific. In contrast to the hippocampus, ERK (but not mTOR) signaling is elevated in the neocortex of fragile X mice. Phosphorylation of ribosomal protein S6, typically a downstream target of mTOR, is elevated in the neocortex, despite normal mTOR activity. This is significant in that S6 phosphorylation facilitates translation, correlates with neuronal activation, and is altered in neurodevelopmental disorders. We show that in fragile X mice, S6 is regulated by ERK via the "alternative" S6 kinase p90-ribosomal S6 kinase (RSK), as evidenced by the site of elevated phosphorylation and the finding that ERK inhibition corrects elevated RSK and S6 activity. These findings indicate that signaling networks are altered in the neocortex of fragile X mice such that S6 phosphorylation receives aberrant input from ERK/RSK. Importantly, an RSK inhibitor reduces susceptibility to audio…

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Crossref · 10.1073/pnas.1610812113

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Authors
Sawicka, K., Pyronneau, A., Chao, M., Bennett, M. V. L., & Zukin, R. S.
Affiliations
Albert Einstein College of Medicine (US)
Venue
Proceedings of the National Academy of Sciences
Published
2016-09-23
Volume
113
Issue
41
Pages
E6290-E6297
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
OpenAlex
W2521150881
Cited by
84
References
43
Citations by year
2026: 4 · 2025: 4 · 2024: 9 · 2023: 13 · 2022: 9 · 2021: 5 · 2020: 10 · 2019: 10 · 2018: 15 · 2017: 5
FWCI
8.07
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • HHS | NIH | National Institute of Mental Health (MH092877)
  • |NIH| National Institute of Neurological Diseases and Stroke (NS045693)
  • Evelyn F. McKnight Brain Research Foundation (N/A)
  • NARSAD Distinguished Investigator Award (N/A)
  • F. M. Kirby Foundation (N/A)
  • FRAXA Research Foundation (Postdoctoral fellowship to KS)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Keywords
fragile X syndrome, Fmr1 knockout mice, ERK signaling, p90 ribosomal S6 kinase, S6 phosphorylation, mTOR signaling, protein synthesis, audiogenic seizures, neocortex, hippocampus, brain region specificity, RSK inhibitors, neurodevelopmental disorders
MeSH terms
Animals, Cerebral Cortex, Disease Models, Animal, DNA-Binding Proteins, Fragile X Syndrome, Neurons, Phosphorylation, Seizures, Synapses, Transcription Factors, Signal Transduction, Mice, Knockout, Phosphatidylinositol 3-Kinases, Epilepsy, Reflex, Ribosomal Protein S6 Kinases, 90-kDa, Extracellular Signal-Regulated MAP Kinases, Mice, Fragile X Messenger Ribonucleoprotein 1, TOR Serine-Threonine Kinases

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