Altered levels of the splicing factor muscleblind modifies cerebral cortical function in mouse models of myotonic dystrophy
Myotonic dystrophy (DM) is a progressive, multisystem disorder affecting skeletal muscle, heart, and central nervous system. In both DM1 and DM2, microsatellite expansions of CUG and CCUG RNA repeats, respectively, accumulate and disrupt functions of alternative splicing factors, including musclebli...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2018-04-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996118300032 |
| _version_ | 1818353361562370048 |
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| author | Gang Chen Russell E. Carter John D. Cleary Tammy S. Reid Laura P. Ranum Maurice S. Swanson Timothy J. Ebner |
| author_facet | Gang Chen Russell E. Carter John D. Cleary Tammy S. Reid Laura P. Ranum Maurice S. Swanson Timothy J. Ebner |
| author_sort | Gang Chen |
| collection | DOAJ |
| description | Myotonic dystrophy (DM) is a progressive, multisystem disorder affecting skeletal muscle, heart, and central nervous system. In both DM1 and DM2, microsatellite expansions of CUG and CCUG RNA repeats, respectively, accumulate and disrupt functions of alternative splicing factors, including muscleblind (MBNL) proteins. Grey matter loss and white matter changes, including the corpus callosum, likely underlie cognitive and executive function deficits in DM patients. However, little is known how cerebral cortical circuitry changes in DM. Here, flavoprotein optical imaging was used to assess local and contralateral responses to intracortical motor cortex stimulation in DM-related mouse models. In control mice, brief train stimulation generated ipsilateral and contralateral homotopic fluorescence increases, the latter mediated by the corpus callosum. Single pulse stimulation produced an excitatory response with an inhibitory-like surround response mediated by GABAA receptors. In a mouse model of DM2 (Mbnl2 KO), we observed prolonged and increased responsiveness to train stimulation and loss of the inhibition from single pulse stimulation. Conversely, mice overexpressing human MBNL1 (MBNL1-OE) exhibited decreased contralateral response to train stimulation and reduction of inhibitory-like surround to single pulse stimulation. Therefore, altering levels of two key DM-associated splicing factors modifies functions of local cortical circuits and contralateral responses mediated through the corpus callosum. |
| first_indexed | 2024-12-13T19:08:19Z |
| format | Article |
| id | doaj.art-eeb3a2270fa3499daa4de091a8688dcd |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-13T19:08:19Z |
| publishDate | 2018-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-eeb3a2270fa3499daa4de091a8688dcd2022-12-21T23:34:29ZengElsevierNeurobiology of Disease1095-953X2018-04-011123548Altered levels of the splicing factor muscleblind modifies cerebral cortical function in mouse models of myotonic dystrophyGang Chen0Russell E. Carter1John D. Cleary2Tammy S. Reid3Laura P. Ranum4Maurice S. Swanson5Timothy J. Ebner6Department of Neuroscience, University of Minnesota, Minneapolis, MN, USADepartment of Neuroscience, University of Minnesota, Minneapolis, MN, USACenter for NeuroGenetics, Department of Molecular Genetics & Microbiology and Neurology, College of Medicine, Genetics Institute, University of Florida, Gainesville, FL, USACenter for NeuroGenetics, Department of Molecular Genetics & Microbiology and Neurology, College of Medicine, Genetics Institute, University of Florida, Gainesville, FL, USACenter for NeuroGenetics, Department of Molecular Genetics & Microbiology and Neurology, College of Medicine, Genetics Institute, University of Florida, Gainesville, FL, USACenter for NeuroGenetics, Department of Molecular Genetics & Microbiology and Neurology, College of Medicine, Genetics Institute, University of Florida, Gainesville, FL, USADepartment of Neuroscience, University of Minnesota, Minneapolis, MN, USA; Corresponding author at: Department of Neuroscience, University of Minnesota, Lions Research Building Room 421, 2001 Sixth Street SE, Minneapolis, MN 55455, USA.Myotonic dystrophy (DM) is a progressive, multisystem disorder affecting skeletal muscle, heart, and central nervous system. In both DM1 and DM2, microsatellite expansions of CUG and CCUG RNA repeats, respectively, accumulate and disrupt functions of alternative splicing factors, including muscleblind (MBNL) proteins. Grey matter loss and white matter changes, including the corpus callosum, likely underlie cognitive and executive function deficits in DM patients. However, little is known how cerebral cortical circuitry changes in DM. Here, flavoprotein optical imaging was used to assess local and contralateral responses to intracortical motor cortex stimulation in DM-related mouse models. In control mice, brief train stimulation generated ipsilateral and contralateral homotopic fluorescence increases, the latter mediated by the corpus callosum. Single pulse stimulation produced an excitatory response with an inhibitory-like surround response mediated by GABAA receptors. In a mouse model of DM2 (Mbnl2 KO), we observed prolonged and increased responsiveness to train stimulation and loss of the inhibition from single pulse stimulation. Conversely, mice overexpressing human MBNL1 (MBNL1-OE) exhibited decreased contralateral response to train stimulation and reduction of inhibitory-like surround to single pulse stimulation. Therefore, altering levels of two key DM-associated splicing factors modifies functions of local cortical circuits and contralateral responses mediated through the corpus callosum.http://www.sciencedirect.com/science/article/pii/S0969996118300032Corpus callosumflavoproteinMBNLMicrosatellite repeatsMyotonic dystrophy |
| spellingShingle | Gang Chen Russell E. Carter John D. Cleary Tammy S. Reid Laura P. Ranum Maurice S. Swanson Timothy J. Ebner Altered levels of the splicing factor muscleblind modifies cerebral cortical function in mouse models of myotonic dystrophy Neurobiology of Disease Corpus callosum flavoprotein MBNL Microsatellite repeats Myotonic dystrophy |
| title | Altered levels of the splicing factor muscleblind modifies cerebral cortical function in mouse models of myotonic dystrophy |
| title_full | Altered levels of the splicing factor muscleblind modifies cerebral cortical function in mouse models of myotonic dystrophy |
| title_fullStr | Altered levels of the splicing factor muscleblind modifies cerebral cortical function in mouse models of myotonic dystrophy |
| title_full_unstemmed | Altered levels of the splicing factor muscleblind modifies cerebral cortical function in mouse models of myotonic dystrophy |
| title_short | Altered levels of the splicing factor muscleblind modifies cerebral cortical function in mouse models of myotonic dystrophy |
| title_sort | altered levels of the splicing factor muscleblind modifies cerebral cortical function in mouse models of myotonic dystrophy |
| topic | Corpus callosum flavoprotein MBNL Microsatellite repeats Myotonic dystrophy |
| url | http://www.sciencedirect.com/science/article/pii/S0969996118300032 |
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