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Selective deletion of astroglial FMRP dysregulates glutamate transporter GLT1 and contributes to fragile X syndrome phenotypes in vivo.
Open accessAbstract
UNLABELLED: How the loss of fragile X mental retardation protein (FMRP) in different brain cell types, especially in non-neuron glial cells, induces fragile X syndrome (FXS) phenotypes has just begun to be understood. In the current study, we generated inducible astrocyte-specific Fmr1 conditional knock-out mice (i-astro-Fmr1-cKO) and restoration mice (i-astro-Fmr1-cON) to study the in vivo modulation of FXS synaptic phenotypes by astroglial FMRP. We found that functional expression of glutamate transporter GLT1 is 40% decreased in i-astro-Fmr1-cKO somatosensory cortical astrocytes in vivo, which can be fully rescued by the selective re-expression of FMRP in astrocytes in i-astro-Fmr1-cON mice. Although the selective loss of astroglial FMRP only modestly increases spine density and length in cortical pyramidal neurons, selective re-expression of FMRP in astrocytes significantly attenuates abnormal spine morphology in these neurons of i-astro-Fmr1-cON mice. Moreover, we found that basal protein synthesis levels and immunoreactivity of phosphorylated S6 ribosomal protein (p-s6P) is significantly increased in i-astro-Fmr1-cKO mice, while the enhanced cortical protein synthesis observed in Fmr1 KO mice is mitigated in i-astro-Fmr1-cON mice. Furthermore, ceftriaxone-mediated upregulation of surface GLT1 expression restores functional glutamate uptake and attenuates enhanced neuronal excitability in Fmr1 KO mice. In particular, ceftriaxone significantly decreases the growth rate of abnormally accelerated body weight and completely corrects spine abnormality in Fmr1 KO mice. Together, these results show that the selective loss of astroglial FMRP contributes to cortical synaptic deficits in FXS, presumably through dysregulated astroglial glutamate transporter GLT1 and impaired glutamate uptake. These results suggest the involvement of astrocyte-mediated mechanisms in the pathogenesis of FXS. SIGNIFICANCE STATEMENT: Previous studies to understand how the loss of function of fragile X mental retardation protein (FMRP) causes fragile X syndrome (FXS) have largely focused on neurons; whether the selective loss of astroglial FMRP in vivo alters astrocyte functions and contributes to the pathogenesis of FXS remain essentially unknown. This has become a long-standing unanswered question in the fragile X field, which is also relevant to autism pathogenesis. Our current study generated astrocyte-specific Fmr1 conditional knock-out and restoration mice, and provided compelling evidence that the selective loss of astroglial FMRP contributes to cortical synaptic deficits in FXS, likely through the dysregulated astroglial glutamate transporter GLT1 expression and impaired glutamate uptake. These results demonstrate previously undescribed astrocyte-mediated mechanisms in the pathogenesis of FXS.
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“Astrocyte-specific Fmr1 KO mouse displays reduced expression of the astrocytic glutamate transporter GLT-1, which leads to reduced astrocytic uptake of extracellular glutamate and increased cortical neuronal excitability (Higashimori et al., 2016).”
From Astrocytes in fragile X syndrome (2024) · cites this paper as Higashimori et al., 2016
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“Species specific differences and differences in experimental approaches such as glutamate incubation time may explain different results in studies on astrocytic glutamate uptake (Higashimori et al., 2016; Ren et al., 2023).”
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Metadata
- Authors
- Higashimori, H., Schin, C. S., Chiang, M. S. R., Morel, L., Shoneye, T. A., Nelson, D. L., & Yang, Y.
- Affiliations
- Tufts University (US)
- Baylor College of Medicine (US)
- Venue
- Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2016-07-06
- Volume
- 36
- Issue
- 27
- Pages
- 7079-7094
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC4938857
- OpenAlex
- W2469266539
- Cited by
- 105
- References
- 54
- Citations by year
- 2026: 6 · 2025: 11 · 2024: 13 · 2023: 8 · 2022: 16 · 2021: 15 · 2020: 10 · 2019: 9 · 2018: 10 · 2017: 5 · 2016: 2
- FWCI
- 7.00
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- FRAXA Research Foundation
- Massachusetts Institute of Technology
- Autism Science Foundation
- National Institutes of Health
- Center for Neuroscience Research
- National Institute of Mental Health (R01MH099554, R01MH106490)
- National Institute of General Medical Sciences (R25GM066567)
- National Institute of Neurological Disorders and Stroke (P30NS047243)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD083092)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Keywords
- fragile X syndrome, FMRP, astrocytes, GLT-1, glutamate transporters, glutamate uptake, conditional knockout mice, dendritic spine morphology, cortical pyramidal neurons, protein synthesis, S6 phosphorylation, ceftriaxone, neuronal excitability, synaptic dysfunction
- MeSH terms
- Action Potentials, Age Factors, Animals, Animals, Newborn, Astrocytes, Cerebral Cortex, Disease Models, Animal, Estrogen Antagonists, Fragile X Syndrome, Gene Expression Regulation, Mice, Inbred C57BL, Nerve Tissue Proteins, Tamoxifen, Transcription Factors, Pyramidal Cells, Excitatory Amino Acid Transporter 2, Mice, Fragile X Messenger Ribonucleoprotein 1, Fragile X Mental Retardation Protein, In Vitro Techniques
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