Elevated glycogen synthase kinase-3 activity in Fragile X mice: Key metabolic regulator with evidence for treatment potential
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Significant advances have been made in understanding the underlying defects of and developing potential treatments for Fragile X syndrome (FXS), the most common heritable mental retardation. It has been shown that neuronal metabotropic glutamate receptor 5 (mGluR5)-mediated signaling is affected in FX animal models, with consequent alterations in activity-dependent protein translation and synaptic spine functionality. We demonstrate here that a central metabolic regulatory enzyme, glycogen synthase kinase-3 (GSK3) is present in a form indicating elevated activity in several regions of the FX mouse brain. Furthermore, we show that selective GSK3 inhibitors, as well as lithium, are able to revert mutant phenotypes of the FX mouse. Lithium, in particular, remained effective with chronic administration, although its effects were reversible even when given from birth. The combination of an mGluR5 antagonist and GSK3 inhibitors was not additive. Instead, it was discovered that mGluR5 signaling and GSK3 activation in the FX mouse are coordinately elevated, with inhibition of mGluR5 leading to inhibition of GSK3. These findings raise the possibility that GSK3 is a fundamental and central component of FXS pathology, with a substantial treatment potential.
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Lithium reduces levels of GSK-3β, a protein linked to mGluR1 signaling that is elevated in FXS.
“lithium was shown to decrease the level of glycogen synthase kinase 3β (GSK-3β) linked to mGluR1 signaling and upregulated in FXS (121)”
From Fragile X syndrome: causes, diagnosis, mechanisms, and therapeutics (2012) · cites this paper as [121]
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Torrioli, M., Vernacotola, S., Setini, C., Bevilacqua, F., Martinelli, D., Snape, M., Hutchison, J. A., Di Raimo, F. R., Tabolacci, E., & Neri, G. (2010) · American Journal of Medical Genetics Part A · doi:10.1002/ajmg.a.33484 · Cited by 71 · see citing works
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Elucidation of the GSK3α Structure Informs the Design of Novel, Paralog-Selective Inhibitors
Amaral, B., Capacci, A., Anderson, T., Tezer, C., Bajrami, B., Lulla, M., Lucas, B., Chodaparambil, J. V., Marcotte, D., Kumar, P. R., et al. (2023) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.2c00476 · Cited by 22 · see citing works
- Authors
- Min, W. W., Yuskaitis, C. J., Yan, Q., Sikorski, C., Chen, S., Jope, R. S., & Bauchwitz, R. P.
- Affiliations
- Columbia University (US)
- University of Alabama at Birmingham (US)
- Corresponding author
- Bauchwitz, Robert P.
- Venue
- Neuropharmacology
- Publisher
- Elsevier BV
- Published
- 2009-02
- Volume
- 56
- Issue
- 2
- Pages
- 463-472
- ISSN
- 0028-3908 (ISSN-L)
- PMC
- PMC2707186
- OpenAlex
- W2111005485
- Cited by
- 146
- References
- 88
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 4 · 2023: 6 · 2022: 6 · 2021: 9 · 2020: 5 · 2019: 9 · 2018: 3 · 2017: 6 · 2016: 8 · 2015: 7 · 2014: 15 · 2013: 22 · 2012: 13
- FWCI
- 5.51
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Neuropharmacology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- CogPrints (University of Southampton) (submittedVersion)
- Funders
- FRAXA Research Foundation
- National Institutes of Health
- National Institute of Mental Health (MH38752, R56MH038752, R01MH038752)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
- Keywords
- fragile X syndrome, glycogen synthase kinase-3, lithium, GSK-3 inhibitors, intellectual disability, metabotropic glutamate receptors, synaptic plasticity, enzyme activity
- MeSH terms
- Acoustic Stimulation, Analysis of Variance, Animals, Brain, Citrates, Disease Models, Animal, Dose-Response Relationship, Drug, Drug Administration Routes, Enzyme Inhibitors, Exploratory Behavior, Gene Expression Regulation, Indoles, Male, Maleimides, Pyridines, Seizures, Serine, Thiazoles, Urea, Lithium Chloride, Mice, Knockout, Excitatory Amino Acid Antagonists, Antimanic Agents, Glycogen Synthase Kinase 3, Mice, Fragile X Messenger Ribonucleoprotein 1
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