ArticleProceedings of the National Academy of Sciences of the United States of America2016
Elevated ERK/p90 ribosomal S6 kinase activity underlies audiogenic seizure susceptibility in fragile X mice.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 51 papers.
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Who cites it
51 citing papers in PubMed, 83 citations in OpenAlex.
- The Role of the Immunoglobulin Superfamily of Cell Adhesion Molecules in Intellectual Disability.Cells · 2026Review
- Dentate Gyrus ERK1/2-BDNF Signaling is Required for the Antidepressant Effect of Microglial Stimulation in a Male Mouse Model of Depression Induced by Adolescent Nicotine Exposure.Neurochemical research · 2026Article
- Contribution of astrocytic calcium signaling to auditory hypersensitivity in a mouse model of fragile X syndrome.Neurobiology of disease · 2026Article
- Suppression of astrocyte BMP signaling improves molecular signatures and functional deficits in a fragile X syndrome mouse model.Nature communications · 2026Article
- Altered Auditory Maturation in Fragile X Syndrome and Its Involvement in Audiogenic Seizure Susceptibility.Autism research : official journal of the International Society for Autism Research · 2026Article
- Fate plasticity of interneuron specification.iScience · 2025Article
- Drug Treatments for Neurodevelopmental Disorders: Targeting Signaling Pathways and Homeostasis.Current neurology and neuroscience reports · 2024Review
- RSK1 and RSK2 as therapeutic targets: an up-to-date snapshot of emerging data.Expert opinion on therapeutic targets · 2024Review
- Therapeutic efficacy of the BKCa channel opener chlorzoxazone in a mouse model of Fragile X syndrome.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2024Article
- A Two-Hit Approach Inducing Flurothyl Seizures in Fmr1 Knockout Mice Impacts Anxiety and Repetitive Behaviors.Brain sciences · 2024Article
- SRC family kinase inhibition rescues molecular and behavioral phenotypes, but not protein interaction network dynamics, in a mouse model of Fragile X syndrome.Molecular psychiatry · 2024Article
- miR-483-5p orchestrates the initiation of protein synthesis by facilitating the decrease in phosphorylated Ser209eIF4E and 4E-BP1 levels.Scientific reports · 2024Article
- Growth-suppressor microRNAs mediate synaptic overgrowth and behavioral deficits in Fragile X mental retardation protein deficiency.iScience · 2024Article
- Epileptic seizures induced by pentylenetetrazole kindling accelerate Alzheimer-like neuropathology in 5×FAD mice.Frontiers in pharmacology · 2024Article
- Cerebellar contribution to autism-relevant behaviors in fragile X syndrome models.Cell reports · 2023Article
- Tau reduction attenuates autism-like features in Fmr1 knockout mice.Molecular autism · 2023Article
- PLPPR4 haploinsufficiency causes neurodevelopmental disorders by disrupting synaptic plasticity via mTOR signalling.Journal of cellular and molecular medicine · 2023Article
- Quantitative proteomics and phosphoproteomics of PPP2R5D variants reveal deregulation of RPS6 phosphorylation through converging signaling cascades.bioRxiv : the preprint server for biology · 2023Article
- Aggression Results in the Phosphorylation of ERK1/2 in the Nucleus Accumbens and the Dephosphorylation of mTOR in the Medial Prefrontal Cortex in Female Syrian Hamsters.International journal of molecular sciences · 2023Article
- Progranulin is an FMRP target that influences macroorchidism but not behaviour in a mouse model of Fragile X Syndrome.Current research in neurobiology · 2023Article
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
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 audiogenic seizures in fragile X mice. Our findings identify RSK as a therapeutic target for fragile X and suggest the therapeutic potential of drugs for the treatment of FXS may vary in a brain-region-specific manner.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.