Wild-type MECP2 expression coincides with age-dependent sensory phenotypes in a female mouse model for Rett syndrome

Abstract

Rett syndrome is characterized by an early period of typical development and then, regression of learned motor and speech skills in girls. The underlying mechanisms from normalcy to regression are unclear. Due to random X-chromosome inactivation, female patients of Rett syndrome, and female mouse models of Rett syndrome (Mecp2Heterozygous, Het) express a functional copy of wild-type MECP2 protein in half of all mature cells in brain and body. By analyzing wild-type MECP2 expression in the context of whisker tactile sensory perception, here we report compensatory increase in MECP2 protein expression in 6-week-old adolescent Het mice, which display normal levels of perineuronal net expression, mild tactile sensory perception deficit and efficient pup retrieval behavior. Comparatively, 12-week-old adult Het mice display decreased MECP2 expression and significant tactile sensory perception deficits. Thus, we have identified a period of normalcy and regression in this female mouse model, which coincide with variable wild-type expression of MECP2. We speculate that compensatory increases in MECP2 expression in Het brains allows for normal functioning, while the inability to maintain these expression level changes leads to behavioral deficits.

Multidimensional analysis of a social behavior identifies regression and phenotypic heterogeneity in a female mouse model for Rett syndrome

“…The pup retrieval task was performed as previously described (Mykins et al, 2023;Stevenson et al, 2021). Two 6week-old or 10-12 week-old naïve female littermates (one WT and one Het) with no prior experience of pup retrieval were co-housed with a pregnant CBA/CaJ female (10-12 weeks of age) 3-5 days before birth.…”

“…Preclinical Mecp2 rodent models recapitulate many of the phenotypic features of RTT such as sensory processing, social communication, and motor deficits (Durand et al, 2012;Goffin et al, 2012;Ito-Ishida et al, 2015;Krishnan et al, 2017;Lee et al, 2017;Lo et al, 2016;Mykins et al, 2023;Orefice et al, 2016;Stevenson et al, 2021;Su et al, 2015;Veeraragavan et al, 2016;Xu et al, 2022). Thus far, three other published papers have shown possible regression phenotypes, for breathing abnormalities in a mouse conditional knockout model, learned forepaw skill involving seed opening in a female rat model, and in skilled motor learning in female mice (Achilly, Wang, et al, 2021;Huang et al, 2016;Veeraragavan et al, 2016).…”

“…Towards this end, we have established an ethologically relevant social behavioral assay called pup retrieval task as a model to study cellular and neural circuitry basis for social cognition, complex sensorimotor integration and experience-dependent plasticity (Dvorkin & Shea, 2022;Krishnan et al, 2015Krishnan et al, , 2017Lau, Layo, et al, 2020;Mykins et al, 2023;Stevenson et al, 2021;Xie et al, 2023). During this task, female mice integrate sensory cues to execute goal-directed motor sequences to retrieve scattered pups back to their home nest (Alsina-Llanes et al, 2015;Beach & Jaynes, 1956;Champagne et al, 2007;Champagne & Curley, 2016;Dunlap et al, 2020;Hemel, 1973;Koch & Ehret, 1989;Lonstein et al, 2015;Marlin et al, 2015;Stern, 1996;Stern & Mackinnon, 1978).…”

“…During this task, female mice integrate sensory cues to execute goal-directed motor sequences to retrieve scattered pups back to their home nest (Alsina-Llanes et al, 2015;Beach & Jaynes, 1956;Champagne et al, 2007;Champagne & Curley, 2016;Dunlap et al, 2020;Hemel, 1973;Koch & Ehret, 1989;Lonstein et al, 2015;Marlin et al, 2015;Stern, 1996;Stern & Mackinnon, 1978). Using end-point metrics such as latency index and errors during retrieval, we found that 6 weekold adolescent Mecp2-heterozygous female mice (Het) were as efficient at pup retrieval as wild-type littermate controls (WT), and 12 week-old adult Het were inefficient at retrieval (Krishnan et al, 2017;Mykins et al, 2023;Stevenson et al, 2021). However, movement sequences during social behaviors are dynamic over time, with distinct behavioral sequences that are often ignored due to their inherent complexity (Stevenson et al, 2021).…”

Sensory experiences questionnaire unravels differences in sensory profiles between MECP2‐related disorders

“…Similarly, Rett mice models exhibit significant latency differences in auditory pathways (Liao et al, 2012). Mouse models of Rett also exhibit deficits in tactile sensory perception as measured in the primary somatosensory cortex (Mykins et al, 2023), postnatal refinement of olfactory circuits (Degano et al, 2014), and discriminating stimulus patterns (LeBlanc et al, 2015). All these studies provide evidence that sensory pathways are globally affected in MECP2-related disorders, although direct comparison of MECP2 duplication to loss of MECP2 has not been reported.…”