Progressive neuroanatomical changes caused by Grin1 loss-of-function mutation
| Autor: | Ali Salahpour, Yuanye Yan, R. Mark Henkelman, Rehnuma Islam, Matthijs C. van Eede, Amy J. Ramsey, Marija Milenkovic, Katheron Intson |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Male medicine.medical_specialty Mice 129 Strain GluN1 GRIN1 Autism Encephalopathy Substantia nigra Mice Transgenic Nerve Tissue Proteins Striatum Biology Receptors N-Methyl-D-Aspartate lcsh:RC321-571 White matter 03 medical and health sciences Mice 0302 clinical medicine Loss of Function Mutation Internal medicine medicine Animals lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry NR1 Dopaminergic Neurons Dopaminergic Age Factors Brain Organ Size medicine.disease Mice Inbred C57BL 030104 developmental biology Endocrinology medicine.anatomical_structure Neurology nervous system NMDA biology.protein GRIN2A GRIN2B 030217 neurology & neurosurgery |
| Zdroj: | Neurobiology of Disease, Vol 132, Iss, Pp-(2019) |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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