Altered levels of the splicing factor muscleblind modifies cerebral cortical function in mouse models of myotonic dystrophy

Gang Chen, Russell E. Carter, John D. Cleary, Tammy S. Reid, Laura P. Ranum, Maurice S. Swanson, Timothy J. Ebner

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)35-48
Number of pages14
JournalNeurobiology of Disease
StatePublished - Apr 2018

Bibliographical note

Funding Information:
We thank Lijuan Zhuo, Christopher Chamberlain, Michael Haenish, David Deal, and Myrna Stenberg for animal preparation. This work was supported by the National Institute of Neurological Disorders and Stroke at the National Institutes of Health grant P01 NS058901 to L.P.R., M.S.S. and T.J.E.

Publisher Copyright:
© 2018


  • Corpus callosum
  • MBNL
  • Microsatellite repeats
  • Myotonic dystrophy
  • flavoprotein


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