Structural and functional differences in the barrel cortex of Mecp2 null mice

Abstract

Functional deficits in sensory systems are commonly noted in neurodevelopmental disorders, such as the Rett syndrome (RTT). Defects in methyl CpG binding protein gene (MECP2) largely accounts for RTT. Manipulations of the Mecp2 gene in mice provide useful models to probe into various aspects of brain development associated with the RTT. In this study, we focused on the somatosensory cortical phenotype in the Bird mouse model of RTT. We used voltage-sensitive dye imaging to evaluate whisker sensory evoked activity in the barrel cortex of mice. We coupled this functional assay with morphological analyses in postnatal mice and investigated the dendritic differentiation of barrel neurons and individual thalamocortical axon (TCA) arbors that synapse with them. We show that in Mecp2-deficient male mice, whisker-evoked activity is roughly topographic but weak in the barrel cortex. At the morphological level, we find that TCA arbors fail to develop into discrete, concentrated patches in barrel hollows, and the complexity of the dendritic branches in layer IV spiny stellate neurons is reduced. Collectively, our results indicate significant structural and functional impairments in the barrel cortex of the Bird mouse line, a popular animal model for the RTT. Such structural and functional anomalies in the primary somatosensory cortex may underlie orofacial tactile sensitivity issues and sensorimotor stereotypies characteristic of RTT.

Quantitative proteomic analysis shows alterations in patient Rett syndrome iPSC cultures at early neuronal progenitor stages

“…Previous study in MeCP2 deficient mice also found altered proteins associated to development and morphology of neurons as well as metabolism [33]. While the proteomic alterations found are relatively small (1.3 fold-change), they are in line with previous studies showing dysregulation of dendrites and axons in RTT patients/mouse models [34][35][36][37] as well as in the juvenile RTT brain [38][39][40]. Although neuronal progenitors did not develop dendrites or axons at these time points yet, our findings indicate that proteins involved in these processes are already expressed and altered in Network analysis using GeneMANIA [41] revealed part of these proteins to be interacting with MeCP2.…”

Quantitative proteomic alterations of human iPSC-based neuronal development indicate early onset of Rett syndrome

“…Proteins that are down regulated in RTT are involved in ‘nervous system development’, ‘forebrain development’ as well as ‘histone methylation’, which has classical roles with MeCP2 in its organization [35]. While the proteomic alterations found are relatively small (1.3 fold-change), they are in line with previous studies showing dysregulation of dendrites and axons in RTT patients/mouse models [33, 36-38] as well as in the juvenile RTT brain [39-41]. Although at these time points of neuronal stem cells did not develop dendrites or axons yet, our findings indicate that proteins involved in these processes are already expressed and altered in RTT at early developmental stages.…”

Structural Bases of Atypical Whisker Responses in a Mouse Model of CDKL5 Deficiency Disorder

“…Reduced cortical responsiveness to visual and auditory stimuli were previously reported in Cdkl5 mutants (Mazziotti et al, 2017;Wang et al, 2012). Remarkably, several animal models of ASD, such as fragile X mental retardation protein 1 (Fmr1), Engrailed-2 (En2), and (Mecp2) mutant mice, exhibit abnormal sensitivity to somatosensory stimuli (Chelini et al, 2018;He et al, 2017;Orefice et al, 2016;Zhang et al, 2014), together with functional connectivity defects in sensory brain areas (Chelini et al, 2018;Haberl et al, 2015;Lee et al, 2017;Zerbi et al, 2018).…”