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Featured ArticleArticles, Development/Plasticity/Repair

Selective Deletion of Astroglial FMRP Dysregulates Glutamate Transporter GLT1 and Contributes to Fragile X Syndrome Phenotypes In Vivo

Haruki Higashimori, Christina S. Schin, Ming Sum R. Chiang, Lydie Morel, Temitope A. Shoneye, David L. Nelson and Yongjie Yang
Journal of Neuroscience 6 July 2016, 36 (27) 7079-7094; DOI: https://doi.org/10.1523/JNEUROSCI.1069-16.2016
Haruki Higashimori
1Tufts University, Department of Neuroscience, Boston, Massachusetts 02111,
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Christina S. Schin
1Tufts University, Department of Neuroscience, Boston, Massachusetts 02111,
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Ming Sum R. Chiang
1Tufts University, Department of Neuroscience, Boston, Massachusetts 02111,
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Lydie Morel
1Tufts University, Department of Neuroscience, Boston, Massachusetts 02111,
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Temitope A. Shoneye
1Tufts University, Department of Neuroscience, Boston, Massachusetts 02111,
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David L. Nelson
2Department of Molecular and Human Genetics, Jan and Dan Duncan Neurological Research Institute, Baylor College of Medicine, Houston, Texas 77030, and
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Yongjie Yang
1Tufts University, Department of Neuroscience, Boston, Massachusetts 02111,
3Tufts University, Sackler School of Biomedical Sciences, Boston, Massachusetts 02111
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Abstract

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.

  • astrocyte
  • autism
  • FMRP
  • fragile X
  • glutamate transporter
  • protein synthesis
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The Journal of Neuroscience: 36 (27)
Journal of Neuroscience
Vol. 36, Issue 27
6 Jul 2016
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Selective Deletion of Astroglial FMRP Dysregulates Glutamate Transporter GLT1 and Contributes to Fragile X Syndrome Phenotypes In Vivo
Haruki Higashimori, Christina S. Schin, Ming Sum R. Chiang, Lydie Morel, Temitope A. Shoneye, David L. Nelson, Yongjie Yang
Journal of Neuroscience 6 July 2016, 36 (27) 7079-7094; DOI: 10.1523/JNEUROSCI.1069-16.2016

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Selective Deletion of Astroglial FMRP Dysregulates Glutamate Transporter GLT1 and Contributes to Fragile X Syndrome Phenotypes In Vivo
Haruki Higashimori, Christina S. Schin, Ming Sum R. Chiang, Lydie Morel, Temitope A. Shoneye, David L. Nelson, Yongjie Yang
Journal of Neuroscience 6 July 2016, 36 (27) 7079-7094; DOI: 10.1523/JNEUROSCI.1069-16.2016
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Keywords

  • astrocyte
  • autism
  • FMRP
  • fragile X
  • glutamate transporter
  • protein synthesis

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