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Updated: Aug 29, 2025
Dissecting Cell-Autonomous Function of Fragile X Mental Retardation Protein in an Auditory Circuit by In Ovo Electroporation
Published on: July 6, 2022
FMRP-related retinal phenotypes: Evidence of glutamate-glutamine metabolic cycle impairment
Maryvonne Ardourel1, Arnaud Pâris1, Chloé Felgerolle1
1UMR7355, CNRS, Orléans, France; Experimental and Molecular Immunology and Neurogenetics, University of Orléans, 3b rue de la Ferollerie, F-45071, Orléans Cedex 2, France.
Abstract:
FMRP, the fragile X mental retardation protein coded by the FMR1 gene, is an RNA-binding protein that assists transport, stabilization and translational regulation of specific synaptic mRNAs. Its expression has been found in multiple cell types of central nervous system (CNS) including glial cells where its involvement in glutamate neurotransmitter homeostasis have been shown. Indeed, glutamate homeostasis deficit has been observed in absence of FMRP in-vivo in cortex and hippocampus structures as well as in vitro on astroglial cell culture. Interestingly, the retina which is an extension of the CNS is presenting electrophysiological alterations in absence of FMRP in both human and murine models suggesting neurotransmitter impairments. Therefore, we investigate the consequences of Fmrp absence on Glutamate-Glutamine cycle in whole retinas and primary retinal Müller cells culture which are the main glial cells of the retina. Using the Fmr1-/y mice, we have shown in vivo and in vitro that the absence of Fmrp in Müller cells is characterized by loss of Glutamate-Glutamine cycle homeostasis due to a lower Glutamine Synthetase protein expression and activity. The lack of Fmrp in the retina induces a reduced flow of glutamine synthesis. Our data established for the first time in literature a direct link between the lack of Fmrp and neurotransmitter homeostasis in the retina.
Insights
The fragile X mental retardation protein (FMRP) absence disrupts retinal glutamate-glutamine homeostasis. Lack of FMRP in Müller glial cells reduces glutamine synthesis, impacting neurotransmitter balance.
Area of Science:
- Neuroscience
- Molecular Biology
- Glial Cell Biology
Background:
- Fragile X mental retardation protein (FMRP) is crucial for synaptic mRNA regulation in the central nervous system (CNS).
- FMRP's role in glutamate homeostasis is established in CNS structures like the cortex and hippocampus, and in astroglial cells.
- Electrophysiological alterations in the retina of FMRP-deficient models suggest impaired neurotransmission.
Purpose of the Study:
- To investigate the impact of FMRP absence on the glutamate-glutamine cycle in the retina.
- To examine FMRP's role in Müller cells, the primary glial cells in the retina.
Main Methods:
- Utilized Fmr1 knockout (Fmr1-/y) mice for in vivo and in vitro studies.
- Analyzed whole retinas and primary retinal Müller cell cultures.
- Assessed Glutamine Synthetase protein expression and activity.
Main Results:
- Absence of FMRP in retinal Müller cells leads to a loss of glutamate-glutamine cycle homeostasis.
- Significantly lower Glutamine Synthetase protein expression and activity were observed in FMRP-deficient retinas.
- FMRP deficiency results in reduced glutamine synthesis flow within the retina.
Conclusions:
- Established a direct link between FMRP deficiency and impaired neurotransmitter homeostasis in the retina.
- Demonstrated that FMRP is essential for maintaining glutamate-glutamine cycle balance in retinal Müller cells.
- Highlighted the potential for FMRP dysfunction to contribute to retinal abnormalities.
