Rett Syndrome (RTT), a progressive neurological disorder characterized by developmental regression and loss of motor and language skills, is caused by mutations in the X-linked gene encoding methyl-CpG binding protein 2 (MECP2). Neurostructural phenotypes including decreased neuronal size, dendritic complexity, and spine density have been reported in postmortem RTT brain tissue and in Mecp2 animal models. How these changes in neuronal morphology are related to RTT-like phenotype and MeCP2 function, and the extent to which restoration of neuronal morphology can be used as a cellular readout in therapeutic studies, however, remain unclear. Here, we systematically examined neuronal morphology in vivo across three Mecp2 mouse models representing Mecp2 loss-of-function, partial loss-of-function, and gain-of-function mutations, at developmental time points corresponding to early- and late-symptomatic RTT-like behavioral phenotypes. We found that in Mecp2 loss-of-function mouse models, dendritic complexity is reduced in a mild, age-dependent, and brain region-specific manner, whereas soma size is reduced consistently throughout development. Neither phenotype, however, is altered in Mecp2 gain-of-function mice. Our results suggest that, in the cell types we examined, the use of dendritic morphology as a cellular readout of RTT phenotype and therapeutic efficacy should be cautioned, as it is intrinsically variable. In contrast, soma size may be a robust and reliable marker for evaluation of MeCP2 function in Mecp2 loss-of-function studies.
Keywords: Dendritic branching; MECP2; Mouse model; Neuronal morphology; Rett syndrome; Soma size.
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