Elevated ERK/p90 ribosomal S6 kinase activity underlies audiogenic seizure susceptibility in fragile X mice
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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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The mTor pathway is enhanced in Fmr1-knockout neurons.
“Conversely, it was reported that the mTor pathway is enhanced in Fmr1-knockout neurons (Sharma et al., 2010; Sawicka et al., 2016).”
From New insights into the regulatory function of CYFIP1 in the context of WAVE- and FMRP-containing complexes (2017) · cites this paper as Sawicka et al., 2016
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Therapeutic efficacy of the BKCa channel opener chlorzoxazone in a mouse model of Fragile X syndrome
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Drug Treatments for Neurodevelopmental Disorders: Targeting Signaling Pathways and Homeostasis
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Pharmacological Treatments for Fragile X Syndrome Based on Synaptic Dysfunction
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Additional file 1 of Tau reduction attenuates autism-like features in Fmr1 knockout mice
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The Role of the Immunoglobulin Superfamily of Cell Adhesion Molecules in Intellectual Disability
Zaman, N., Bui, K., & Sytnyk, V. (2026) · Cells · doi:10.3390/cells15191801
- 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
- Publisher
- National Academy of Sciences
- Published
- 2016-09-23
- Volume
- 113
- Issue
- 41
- Pages
- E6290-E6297
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC5068319
- 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
- green
- www.ncbi.nlm.nih.gov
- 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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