Progressive neuroanatomical changes caused by Grin1 loss-of-function mutation
NMDA receptor dysfunction is central to the encephalopathies caused by missense mutations in the NMDA receptor subunit genes. Missense variants of GRIN1, GRIN2A, and GRIN2B cause similar syndromes with varying severity of intellectual impairment, autism, epilepsy, and motor dysfunction. To gain insi...
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| Format: | Article |
| Language: | English |
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Elsevier
2019-12-01
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| Series: | Neurobiology of Disease |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996119301950 |
| _version_ | 1819120128381419520 |
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| author | Katheron Intson Matthijs C. van Eede Rehnuma Islam Marija Milenkovic Yuanye Yan Ali Salahpour R. Mark Henkelman Amy J. Ramsey |
| author_facet | Katheron Intson Matthijs C. van Eede Rehnuma Islam Marija Milenkovic Yuanye Yan Ali Salahpour R. Mark Henkelman Amy J. Ramsey |
| author_sort | Katheron Intson |
| collection | DOAJ |
| description | NMDA receptor dysfunction is central to the encephalopathies caused by missense mutations in the NMDA receptor subunit genes. Missense variants of GRIN1, GRIN2A, and GRIN2B cause similar syndromes with varying severity of intellectual impairment, autism, epilepsy, and motor dysfunction. To gain insight into possible biomarkers of NMDAR hypofunction, we asked whether a loss-of-function variant in the Grin1 gene would cause structural changes in the brain that could be detected by MRI. We also studied the developmental trajectory of these changes to determine whether structural changes coincided with reported cognitive impairments in the mice. We performed magnetic resonance imaging in male Grin1−/− knockdown mice (GluN1KD) that were three, six, or twelve weeks old. Deformation-based morphometry was used to assess neuroanatomical differences. Volumetric reductions were detected in substantia nigra and striatum of GluN1KD mice at all ages. Changes in limbic structures were only evident at six weeks of age. Reductions in white matter volumes were first evident at three weeks, and additional deficits were detected at six and twelve weeks. FluoroJade immunofluorescence revealed degenerating neurons in twelve-week old GluN1KD mice. We conclude that Grin1 loss-of-function mutations cause volume reductions in dopaminergic structures early in development, while changes to limbic and white matter structures are delayed and are more pronounced in post-adolescent ages. The evidence of degenerating neurons in the mature brain indicates an ongoing process of cell loss as a consequence of NMDAR hypofunction. |
| first_indexed | 2024-12-22T06:15:44Z |
| format | Article |
| id | doaj.art-1f399d1024d0435db10198f2f5a71629 |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-22T06:15:44Z |
| publishDate | 2019-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-1f399d1024d0435db10198f2f5a716292022-12-21T18:36:06ZengElsevierNeurobiology of Disease1095-953X2019-12-01132Progressive neuroanatomical changes caused by Grin1 loss-of-function mutationKatheron Intson0Matthijs C. van Eede1Rehnuma Islam2Marija Milenkovic3Yuanye Yan4Ali Salahpour5R. Mark Henkelman6Amy J. Ramsey7Department of Pharmacology & Toxicology, University of Toronto, 1 King's College Circle, Medical Sciences Building, Toronto, ON, CanadaMouse Imaging Centre, Hospital for Sick Children, 25 Orde Street, Toronto, ON, CanadaDepartment of Physiology, University of Toronto, Toronto, ON, CanadaDepartment of Pharmacology & Toxicology, University of Toronto, 1 King's College Circle, Medical Sciences Building, Toronto, ON, CanadaDepartment of Pharmacology & Toxicology, University of Toronto, 1 King's College Circle, Medical Sciences Building, Toronto, ON, CanadaDepartment of Pharmacology & Toxicology, University of Toronto, 1 King's College Circle, Medical Sciences Building, Toronto, ON, CanadaMouse Imaging Centre, Hospital for Sick Children, 25 Orde Street, Toronto, ON, CanadaDepartment of Pharmacology & Toxicology, University of Toronto, 1 King's College Circle, Medical Sciences Building, Toronto, ON, Canada; Department of Physiology, University of Toronto, Toronto, ON, Canada; Corresponding author at: University of Toronto, 1 Kings College Circle, Medical Sciences Building, Rm 4302, Toronto, ON, Canada.NMDA receptor dysfunction is central to the encephalopathies caused by missense mutations in the NMDA receptor subunit genes. Missense variants of GRIN1, GRIN2A, and GRIN2B cause similar syndromes with varying severity of intellectual impairment, autism, epilepsy, and motor dysfunction. To gain insight into possible biomarkers of NMDAR hypofunction, we asked whether a loss-of-function variant in the Grin1 gene would cause structural changes in the brain that could be detected by MRI. We also studied the developmental trajectory of these changes to determine whether structural changes coincided with reported cognitive impairments in the mice. We performed magnetic resonance imaging in male Grin1−/− knockdown mice (GluN1KD) that were three, six, or twelve weeks old. Deformation-based morphometry was used to assess neuroanatomical differences. Volumetric reductions were detected in substantia nigra and striatum of GluN1KD mice at all ages. Changes in limbic structures were only evident at six weeks of age. Reductions in white matter volumes were first evident at three weeks, and additional deficits were detected at six and twelve weeks. FluoroJade immunofluorescence revealed degenerating neurons in twelve-week old GluN1KD mice. We conclude that Grin1 loss-of-function mutations cause volume reductions in dopaminergic structures early in development, while changes to limbic and white matter structures are delayed and are more pronounced in post-adolescent ages. The evidence of degenerating neurons in the mature brain indicates an ongoing process of cell loss as a consequence of NMDAR hypofunction.http://www.sciencedirect.com/science/article/pii/S0969996119301950GRIN1GluN1NR1NMDAEncephalopathyAutism |
| spellingShingle | Katheron Intson Matthijs C. van Eede Rehnuma Islam Marija Milenkovic Yuanye Yan Ali Salahpour R. Mark Henkelman Amy J. Ramsey Progressive neuroanatomical changes caused by Grin1 loss-of-function mutation Neurobiology of Disease GRIN1 GluN1 NR1 NMDA Encephalopathy Autism |
| title | Progressive neuroanatomical changes caused by Grin1 loss-of-function mutation |
| title_full | Progressive neuroanatomical changes caused by Grin1 loss-of-function mutation |
| title_fullStr | Progressive neuroanatomical changes caused by Grin1 loss-of-function mutation |
| title_full_unstemmed | Progressive neuroanatomical changes caused by Grin1 loss-of-function mutation |
| title_short | Progressive neuroanatomical changes caused by Grin1 loss-of-function mutation |
| title_sort | progressive neuroanatomical changes caused by grin1 loss of function mutation |
| topic | GRIN1 GluN1 NR1 NMDA Encephalopathy Autism |
| url | http://www.sciencedirect.com/science/article/pii/S0969996119301950 |
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