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Longitudinal PET studies of mGluR5 in FXS using an FMR1 knockout mouse model
Sepideh Afshar1, Sevda Lule2, Gengyang Yuan1
1Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, 02129 MA, United States of America.
Abstract:
Fragile X syndrome (FXS) is a monogenic disorder characterized by intellectual disability and behavioral challenges. It is caused by aberrant methylation of the fragile X mental retardation 1 (FMR1) gene. Given the failure of clinical trials in FXS and growing evidence of a role of metabotropic glutamate subtype 5 receptors (mGluR5) in the pathophysiology of the disorder, we investigated mGluR5 function in FMR1 Knockout (FMR1-KO) mice and age- and sex-matched control mice using longitudinal positron emission tomography (PET) imaging to better understand the disorder. The studies were repeated at four time points to examine age- and disease-induced changes in mGluR5 availability using 3-fluoro-[18F]5-(2-pyridinylethynyl)benzonitrile ([18F]FPEB). We found that the binding potential (BP) of [18F]FPEB was significantly lower in the KO mice in mGluR5-implicated brain areas including striatum, cortex, hippocampus, thalamus, and olfactory bulb. The BP also changed with age, regardless of disorder status, increasing in early adulthood in male but not in female mice before decreasing later in both sexes. The difference in mGluR5 availability between the FMR1-KO and control mice and the change in BP in the KO mice as a function of age and sex illustrate the nature of the disorder and its progression, providing mechanistic insights for treatment design.
Insights
Fragile X syndrome (FXS) involves altered metabotropic glutamate 5 receptors (mGluR5) in Fragile X mental retardation 1 gene knockout mice. Positron emission tomography revealed lower mGluR5 availability, offering insights for FXS treatment design.
Area of Science:
- Neuroscience
- Genetics
- Medical Imaging
Background:
- Fragile X syndrome (FXS) is a genetic disorder causing intellectual disability and behavioral issues, linked to the FMR1 gene.
- Previous FXS treatments failed, highlighting the need for new therapeutic targets.
- Metabotropic glutamate subtype 5 receptors (mGluR5) are implicated in FXS pathophysiology.
Purpose of the Study:
- To investigate mGluR5 function and availability in Fragile X syndrome using a mouse model.
- To examine age- and sex-dependent changes in mGluR5 availability in FXS.
- To provide mechanistic insights for developing novel FXS treatments.
Main Methods:
- Longitudinal positron emission tomography (PET) imaging was used in FMR1 Knockout (FMR1-KO) mice and controls.
- The radiotracer 3-fluoro-[18F]5-(2-pyridinylethynyl)benzonitrile ([18F]FPEB) measured mGluR5 binding potential (BP).
- Studies were conducted at four time points to track changes over time.
Main Results:
- [18F]FPEB binding potential (BP) was significantly lower in FMR1-KO mice across key brain regions (striatum, cortex, hippocampus, thalamus, olfactory bulb).
- mGluR5 BP increased with age in early adulthood in male mice, then decreased later in both sexes, irrespective of FXS status.
- Age- and sex-dependent alterations in mGluR5 availability were observed in the FMR1-KO model.
Conclusions:
- Reduced mGluR5 availability is a key feature in the FMR1-KO mouse model of FXS.
- Age and sex significantly influence mGluR5 availability, impacting disease progression.
- These findings offer crucial mechanistic insights for targeted FXS therapeutic strategies.
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