The enhancement of activity rescues the establishment of
            <i>Mecp2</i>
            null neuronal phenotypes

Scaramuzza, Linda; Rocco, Giuseppina De; Desiato, Genni; Gigli, Clementina Cobolli; Chiacchiaretta, Martina; Mirabella, Filippo; Pozzi, Davide; Simone, Marco De; Conforti, Paola; Pagani, Massimiliano; Benfenati, Fabio; Cesca, Fabrizia; Bedogni, Francesco; Landsberger, Nicoletta

doi:10.15252/emmm.202012433

Cited by 13 publications

(14 citation statements)

References 93 publications

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“…Early interventions aimed at increasing neuronal activity mitigate disease onset in both male and female mouse models for Rett syndrome. Early administration of Ampakine CX546, a positive modulator of AMPA receptors, from postnatal days 3-9 in male Mecp2 -null mice enhances neuronal activity, prolongs lifespan, delays disease progression, and rescues both motor abilities and spatial memory (Scaramuzza et al, 2021). In Het females, repetitive motor training enhances neuronal activity of task-specific neurons and improves both spatial memory and motor function well into adulthood (Achilly et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

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

Mykins

Layo

Dunn

et al. 2022

Preprint

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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.

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Section: Discussionmentioning

confidence: 99%

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

Mykins

Layo

Dunn

et al. 2022

Preprint

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“…The calcium-target and calcium-regulating signature genes separated the Rett syndrome samples from the healthy control samples in the PC1-PC2 space well (Figure 2A,B). Unsupervised analysis of differentially expressed genes in the mouse model of Rett syndrome did not reveal significantly enriched calcium-related pathways (Supplementary Figure S1A,B); however, it has been previously shown that calcium signaling is implicated in RTT pathology [26,27]. Focusing on the calcium-related differentially expressed genes utilizing the CaDeGB database, we found that in Mecp2-KO mice, 12.5% (four genes) of all differentially expressed genes were calcium-related (Table 2, Supplementary Table S1).…”

Section: Rett Syndrome (Gse105045 Gse128380)mentioning

confidence: 85%

Angelman Syndrome and Angelman-like Syndromes Share the Same Calcium-Related Gene Signatures

Panov

Kaphzan

2021

IJMS

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Angelman-like syndromes are a group of neurodevelopmental disorders that entail clinical presentation similar to Angelman Syndrome (AS). In our previous study, we showed that calcium signaling is disrupted in AS, and we identified calcium-target and calcium-regulating gene signatures that are able to differentiate between AS and their controls in different models. In the herein study, we evaluated these sets of calcium-target and calcium-regulating genes as signatures of AS-like and non-AS-like syndromes. We collected a number of RNA-seq datasets of various AS-like and non-AS-like syndromes and performed Principle Component Analysis (PCA) separately on the two sets of signature genes to visualize the distribution of samples on the PC1–PC2 plane. In addition to the evaluation of calcium signature genes, we performed differential gene expression analyses to identify calcium-related genes dysregulated in each of the studied syndromes. These analyses showed that the calcium-target and calcium-regulating signatures differentiate well between AS-like syndromes and their controls. However, in spite of the fact that many of the non-AS-like syndromes have multiple differentially expressed calcium-related genes, the calcium signatures were not efficient classifiers for non-AS-like neurodevelopmental disorders. These results show that features based on clinical presentation are reflected in signatures derived from bioinformatics analyses and suggest the use of bioinformatics as a tool for classification.

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“…Early interventions aimed at increasing neuronal activity mitigate disease onset in both male and female mouse models for Rett syndrome. Early administration of Ampakine CX546, a positive modulator of AMPA receptors, from postnatal days 3–9 in male Mecp2 ‐null mice enhances neuronal activity, prolongs lifespan, delays disease progression, and rescues both motor abilities and spatial memory (Scaramuzza et al, 2021). In Het females, repetitive motor training enhances neuronal activity of task‐specific neurons and improves both spatial memory and motor function well into adulthood (Achilly et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

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

Mykins

Layo

Dunn

et al. 2023

J of Neuroscience Research

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Rett syndrome is characterized by an early period of typical development and then, regression of learned motor and speech skills in girls. Loss of MECP2 protein is thought to cause Rett syndrome phenotypes. The specific underlying mechanisms from typical developmental trajectory to regression features throughout life are unclear. Lack of established timelines to study the molecular, cellular, and behavioral features of regression in female mouse models is a major contributing factor. Due to random X-chromosome inactivation, female patients with Rett syndrome and female mouse models for Rett syndrome (Mecp2 Heterozygous , Het) express a functional copy of wild-type MECP2 protein in approximately half of all cells. As MECP2 expression is regulated during early postnatal development and experience, we characterized the expression of wild-type MECP2 in the primary somatosensory cortex of female Het mice. Here, we report increased MECP2 levels in non-parvalbumin-positive neurons of 6-week-old adolescent Het relative to age-matched wild-type controls, while also displaying typical levels of perineuronal net expression in the barrel field subregion of the primary somatosensory cortex, mild tactile sensory perception deficits, and efficient pup retrieval behavior. In contrast, 12-week-old adult Het express MECP2 at levels similar to age-matched wild-type mice, show increased perineuronal net expression in the cortex, and display significant tactile sensory perception deficits. Thus, we have identified a set of behavioral metrics and the cellular substrates to study regression during a specific time in the female Het mouse model, which coincides with changes in wild-type MECP2 expression. We speculate that the precocious increase in MECP2 expression within specific cell types of adolescent Het may provide compensatory benefits at the behavioral level, while the inability to further increase MECP2 levels leads to regressive behavioral phenotypes over time.

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The enhancement of activity rescues the establishment of Mecp2 null neuronal phenotypes

Cited by 13 publications

References 93 publications

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

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

Angelman Syndrome and Angelman-like Syndromes Share the Same Calcium-Related Gene Signatures

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

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