Characterization of a mGluR5 Knockout Rat Model with Hallmarks of Fragile X Syndrome
The number of reported cases of neurodevelopmental disorders has increased significantly in the last few decades, but the etiology of these diseases remains poorly understood. There is evidence of a fundamental link between genetic abnormalities and symptoms of autism spectrum disorders (ASDs), and...
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MDPI AG
2022-08-01
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| author | Victoria Dahl Hawley Helmbrecht Ana Rios Sigler Kate Hildahl Holly Sullivan Sanjana Janakiraman Saahiti Jasti Elizabeth Nance |
| author_facet | Victoria Dahl Hawley Helmbrecht Ana Rios Sigler Kate Hildahl Holly Sullivan Sanjana Janakiraman Saahiti Jasti Elizabeth Nance |
| author_sort | Victoria Dahl |
| collection | DOAJ |
| description | The number of reported cases of neurodevelopmental disorders has increased significantly in the last few decades, but the etiology of these diseases remains poorly understood. There is evidence of a fundamental link between genetic abnormalities and symptoms of autism spectrum disorders (ASDs), and the most common monogenetic inheritable form of ASDs is Fragile X Syndrome (FXS). Previous studies indicate that FXS is linked to glutamate signaling regulation by the G-protein-coupled metabotropic glutamate receptor 5 (mGluR5), which has been shown to have a regulatory role in neuroinflammation. We characterized the effect of knocking out mGluR5 in an organism known to have complex cognitive functions—the rat. The heterozygous phenotype is the most clinically relevant; therefore, we performed analysis in heterozygous pups. We showed developmental abnormalities in heterozygous mGluR5 knockout rats, as well as a significant increase in chemokine (C-X-C motif) ligand 1 (CXCL) expression, a hallmark indicator of early onset inflammation. We quantified an increase in microglial density in the knockout pups and quantified morphological phenotypes representative of greater reactivity in the male vs. female and postnatal day 28 heterozygous pups compared to postnatal day 14 heterozygous pups. In response to injury, reactive microglia release matrix metalloproteases, contribute to extracellular matrix (ECM) breakdown, and are responsible for eradicating cellular and molecular debris. In our study, the changes in microglial density and reactivity correlated with abnormalities in the mRNA expression levels of ECM proteins and with the density of perineuronal nets. We saw atypical neuropsychiatric behavior in open field and elevated plus tests in heterozygous pups compared to wild-type litter and age-matched controls. These results demonstrate the pathological potential of the mGluR5 knockout in rats and further support the presence of neuroinflammatory roots in ASDs. |
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| last_indexed | 2024-03-09T23:23:54Z |
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| spelling | doaj.art-e456cff1a7c84e54b0aefc7b8013cc822023-11-23T17:21:55ZengMDPI AGLife2075-17292022-08-01129130810.3390/life12091308Characterization of a mGluR5 Knockout Rat Model with Hallmarks of Fragile X SyndromeVictoria Dahl0Hawley Helmbrecht1Ana Rios Sigler2Kate Hildahl3Holly Sullivan4Sanjana Janakiraman5Saahiti Jasti6Elizabeth Nance7Department of Chemical Engineering, University of Washington, Seattle, WA 98195, USADepartment of Chemical Engineering, University of Washington, Seattle, WA 98195, USADepartment of Bioengineering, University of Washington, Seattle, WA 98105, USADepartment of Chemical Engineering, University of Washington, Seattle, WA 98195, USADepartment of Chemical Engineering, University of Washington, Seattle, WA 98195, USAPaul Allen School of Computer Science and Engineering, University of Washington, Seattle, WA 98195, USADepartment of Biology, University of Washington, Seattle, WA 98195, USADepartment of Chemical Engineering, University of Washington, Seattle, WA 98195, USAThe number of reported cases of neurodevelopmental disorders has increased significantly in the last few decades, but the etiology of these diseases remains poorly understood. There is evidence of a fundamental link between genetic abnormalities and symptoms of autism spectrum disorders (ASDs), and the most common monogenetic inheritable form of ASDs is Fragile X Syndrome (FXS). Previous studies indicate that FXS is linked to glutamate signaling regulation by the G-protein-coupled metabotropic glutamate receptor 5 (mGluR5), which has been shown to have a regulatory role in neuroinflammation. We characterized the effect of knocking out mGluR5 in an organism known to have complex cognitive functions—the rat. The heterozygous phenotype is the most clinically relevant; therefore, we performed analysis in heterozygous pups. We showed developmental abnormalities in heterozygous mGluR5 knockout rats, as well as a significant increase in chemokine (C-X-C motif) ligand 1 (CXCL) expression, a hallmark indicator of early onset inflammation. We quantified an increase in microglial density in the knockout pups and quantified morphological phenotypes representative of greater reactivity in the male vs. female and postnatal day 28 heterozygous pups compared to postnatal day 14 heterozygous pups. In response to injury, reactive microglia release matrix metalloproteases, contribute to extracellular matrix (ECM) breakdown, and are responsible for eradicating cellular and molecular debris. In our study, the changes in microglial density and reactivity correlated with abnormalities in the mRNA expression levels of ECM proteins and with the density of perineuronal nets. We saw atypical neuropsychiatric behavior in open field and elevated plus tests in heterozygous pups compared to wild-type litter and age-matched controls. These results demonstrate the pathological potential of the mGluR5 knockout in rats and further support the presence of neuroinflammatory roots in ASDs.https://www.mdpi.com/2075-1729/12/9/1308neuroinflammationmicrogliaautism spectrum disorders (ASDs)neurodevelopmental disordersextracellular matrixmachine learning |
| spellingShingle | Victoria Dahl Hawley Helmbrecht Ana Rios Sigler Kate Hildahl Holly Sullivan Sanjana Janakiraman Saahiti Jasti Elizabeth Nance Characterization of a mGluR5 Knockout Rat Model with Hallmarks of Fragile X Syndrome Life neuroinflammation microglia autism spectrum disorders (ASDs) neurodevelopmental disorders extracellular matrix machine learning |
| title | Characterization of a mGluR5 Knockout Rat Model with Hallmarks of Fragile X Syndrome |
| title_full | Characterization of a mGluR5 Knockout Rat Model with Hallmarks of Fragile X Syndrome |
| title_fullStr | Characterization of a mGluR5 Knockout Rat Model with Hallmarks of Fragile X Syndrome |
| title_full_unstemmed | Characterization of a mGluR5 Knockout Rat Model with Hallmarks of Fragile X Syndrome |
| title_short | Characterization of a mGluR5 Knockout Rat Model with Hallmarks of Fragile X Syndrome |
| title_sort | characterization of a mglur5 knockout rat model with hallmarks of fragile x syndrome |
| topic | neuroinflammation microglia autism spectrum disorders (ASDs) neurodevelopmental disorders extracellular matrix machine learning |
| url | https://www.mdpi.com/2075-1729/12/9/1308 |
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