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

Abstract

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.

Cortex-wide neural interfacing via transparent polymer skulls

“…6d, Student's t- test, p < 0.001). These results with See-Shells in the awake animal extend previous flavoprotein imaging observations in anesthetized mice showing that microstimulation of the primary motor cortex co-activates homotopic regions via the corpus callosum 29 . Therefore, See-Shells can be used to study the effects of perturbing localized regions and suggest that the arousal state alters cortical dynamics.…”

Cortex-wide neural interfacing via transparent polymer skulls

“…6d, t-test, p < 0.001). These results with See-Shells in the awake animal extend previous flavoprotein imaging observations in anesthetized mice showing that microstimulation of the primary motor cortex co-activates homotopic regions via the corpus callosum 38 . Therefore, See-Shells can be used to study the effects of perturbing localized regions and suggest that the arousal state alters cortical dynamics.…”

“…The digital design methodology used to generate the See-Shells allows easy modifications to fit skull morphologies different from commonly used wild-type mouse strains. As an example, See-Shells were custom designed for the tottering (tg/tg) mouse 38 , a strain that has a mutation in the Cacna1a gene 27,28 and has narrower skulls than C57BL/6 mice of the same age ( Supplementary Fig. 2).…”

Deprivation of Muscleblind-Like Proteins Causes Deficits in Cortical Neuron Distribution and Morphological Changes in Dendritic Spines and Postsynaptic Densities

“…MBNL family proteins are RBPs critical for post-transcriptional regulations (Batra et al, 2015; Taylor et al, 2018). Aside from the RNA toxicity derived from microsatellite repeat expansions including RAN translation and secondary CELF1 upregulation (Wang et al, 2007, 2009; Zu et al, 2011, 2017), MBNL loss of function is essential for causing DM phenotypes(Thomas et al, 2017; Chen et al, 2018; Ramon-Duaso et al, 2019). The 2KO and DKO models have shown their potential and suitability for the investigations of DM brain pathogenesis due to extensive and distinct splicing alterations similar to DM patients (Charizanis et al, 2012; Goodwin et al, 2015).…”