Longitudinal PET studies of mGluR5 in FXS using an FMR1 knockout mouse model
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 glut...
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| Format: | Article |
| Language: | English |
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De Gruyter
2022-04-01
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| Series: | Translational Neuroscience |
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| Online Access: | https://doi.org/10.1515/tnsci-2022-0217 |
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| author | Afshar Sepideh Lule Sevda Yuan Gengyang Qu Xiying Pan Chuzhi Whalen Michael Brownell Anna-Liisa Mody Maria |
| author_facet | Afshar Sepideh Lule Sevda Yuan Gengyang Qu Xiying Pan Chuzhi Whalen Michael Brownell Anna-Liisa Mody Maria |
| author_sort | Afshar Sepideh |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T02:50:15Z |
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| id | doaj.art-f5c57d59bdd8426bb7225e7b72fbefc2 |
| institution | Directory Open Access Journal |
| issn | 2081-6936 |
| language | English |
| last_indexed | 2024-04-12T02:50:15Z |
| publishDate | 2022-04-01 |
| publisher | De Gruyter |
| record_format | Article |
| series | Translational Neuroscience |
| spelling | doaj.art-f5c57d59bdd8426bb7225e7b72fbefc22022-12-22T03:51:02ZengDe GruyterTranslational Neuroscience2081-69362022-04-01131809210.1515/tnsci-2022-0217Longitudinal PET studies of mGluR5 in FXS using an FMR1 knockout mouse modelAfshar Sepideh0Lule Sevda1Yuan Gengyang2Qu Xiying3Pan Chuzhi4Whalen Michael5Brownell Anna-Liisa6Mody Maria7Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, 02129 MA, United States of AmericaDepartment of Pediatrics, Massachusetts General Hospital, Harvard Medical School, Charlestown, 02129 MA, United States of AmericaGordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, 02129 MA, United States of AmericaGordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, 02129 MA, United States of AmericaGordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, 02129 MA, United States of AmericaDepartment of Pediatrics, Massachusetts General Hospital, Harvard Medical School, Charlestown, 02129 MA, United States of AmericaGordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, 02129 MA, United States of AmericaAthinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, 02129 MA, USAFragile 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.https://doi.org/10.1515/tnsci-2022-0217fxspositron emission tomography[18f]fpebmetabotropic glutamate receptor 5mouse model |
| spellingShingle | Afshar Sepideh Lule Sevda Yuan Gengyang Qu Xiying Pan Chuzhi Whalen Michael Brownell Anna-Liisa Mody Maria Longitudinal PET studies of mGluR5 in FXS using an FMR1 knockout mouse model Translational Neuroscience fxs positron emission tomography [18f]fpeb metabotropic glutamate receptor 5 mouse model |
| title | Longitudinal PET studies of mGluR5 in FXS using an FMR1 knockout mouse model |
| title_full | Longitudinal PET studies of mGluR5 in FXS using an FMR1 knockout mouse model |
| title_fullStr | Longitudinal PET studies of mGluR5 in FXS using an FMR1 knockout mouse model |
| title_full_unstemmed | Longitudinal PET studies of mGluR5 in FXS using an FMR1 knockout mouse model |
| title_short | Longitudinal PET studies of mGluR5 in FXS using an FMR1 knockout mouse model |
| title_sort | longitudinal pet studies of mglur5 in fxs using an fmr1 knockout mouse model |
| topic | fxs positron emission tomography [18f]fpeb metabotropic glutamate receptor 5 mouse model |
| url | https://doi.org/10.1515/tnsci-2022-0217 |
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