MECP2 Mutations Research Articles

Literature Cases Summarized Based on Their Polysomnographic Findings in Rett Syndrome.

Rett syndrome (RTT) is a severe and rare neurodevelopmental disorder affecting mostly girls. In RTT, an impaired sleep pattern is a supportive criterion for the diagnosis, yet little is known regarding the sleep structure and sleep respiratory events. Aiming to delineate sleep by aggregating RTT case (series) data from published polysomnographic studies, seventy-four RTT cases were collected from eleven studies up until 6 February 2022 (PROSPERO: CRD 42020198099). We compared the polysomnographic data within RTT stratifications and to a typically developing population. MECP2 cases demonstrated shortened total sleep time (TST) with increased stage N3 and decreased REM sleep. In cases with CDKL5 mutations, TST was longer and they spent more time in stage N1 but less in stage N3 than those cases affected by MECP2 mutations and a typically developing population. Sleep-disordered breathing was confirmed by the abnormal apnea/hypopnea index of 11.92 ± 23.67/h TST in these aggregated cases. No association of sleep structure with chronological age was found. In RTT, the sleep macrostructure of MECP2 versus CDKL5 cases showed differences, particularly regarding sleep stage N3. A severe REM sleep propensity reduction was found. Aberrant sleep cycling, possibly characterized by a poor REM ‘on switch’ and preponderance in slow and high-voltage sleep, is proposed.

Klinefelter syndrome mosaicism in boys with neurodevelopmental disorders: a cohort study and an extension of the hypothesis

BackgroundKlinefelter syndrome is a common chromosomal (aneuploidy) disorder associated with an extra X chromosome in males. Regardless of numerous studies dedicated to somatic gonosomal mosaicism, Klinefelter syndrome mosaicism (KSM) has not been systematically addressed in clinical cohorts. Here, we report on the evaluation of KSM in a large cohort of boys with neurodevelopmental disorders. Furthermore, these data have been used for an extension of the hypothesis, which we have recently proposed in a report on Turner’s syndrome mosaicism in girls with neurodevelopmental disorders.ResultsKlinefelter syndrome-associated karyotypes were revealed in 49 (1.1%) of 4535 boys. Twenty one boys (0.5%) were non-mosaic 47,XXY individuals. KSM was found in 28 cases (0.6%) and manifested as mosaic aneuploidy (50,XXXXXY; 49,XXXXY; 48,XXXY; 48,XXYY; 47,XXY; and 45,X were detected in addition to 47,XXY/46,XY) and mosaic supernumerary marker chromosomes derived from chromosome X (ring chromosomes X and rearranged chromosomes X). It is noteworthy that KSM was concomitant with Rett-syndrome-like phenotypes caused by MECP2 mutations in 5 boys (0.1%).ConclusionOur study provides data on the occurrence of KSM in neurodevelopmental disorders among males. Accordingly, it is proposed that KSM may be a possible element of pathogenic cascades in psychiatric and neurodegenerative diseases. These observations allowed us to extend the hypothesis proposed in our previous report on the contribution of somatic gonosomal mosaicism (Turner’s syndrome mosaicism) to the etiology of neurodevelopmental disorders. Thus, it seems to be important to monitor KSM (a possible risk factor or a biomarker for adult-onset multifactorial brain diseases) and analysis of neuromarkers for aging in individuals with Klinefelter syndrome. Cases of two or more supernumerary chromosomes X were all associated with KSM. Finally, Rett syndrome-like phenotypes associated with KSM appear to be more common in males with neurodevelopmental disorders than previously recognized.

Vitamin D modulates cortical transcriptome and behavioral phenotypes in an Mecp2 heterozygous Rett syndrome mouse model

Rett syndrome (RTT) is an X-linked neurological disorder caused by mutations in the transcriptional regulator MECP2. Mecp2 loss-of-function leads to the disruption of many cellular pathways, including aberrant activation of the NF-κB pathway. Genetically attenuating the NF-κB pathway in Mecp2-null mice ameliorates hallmark phenotypes of RTT, including reduced dendritic complexity, raising the question of whether NF-κB pathway inhibitors could provide a therapeutic avenue for RTT. Vitamin D is a known inhibitor of NF-κB signaling; further, vitamin D deficiency is prevalent in RTT patients and male Mecp2-null mice. We previously demonstrated that vitamin D rescues the aberrant NF-κB activity and reduced neurite outgrowth of Mecp2-knockdown cortical neurons in vitro, and that dietary vitamin D supplementation rescues decreased dendritic complexity and soma size of neocortical projection neurons in both male hemizygous Mecp2-null and female heterozygous mice in vivo. Here, we have identified over 200 genes whose dysregulated expression in the Mecp2+/− cortex is modulated by dietary vitamin D. Genes normalized with vitamin D supplementation are involved in dendritic complexity, synapses, and neuronal projections, suggesting that the rescue of their expression could underpin the rescue of neuronal morphology. Further, there is a disruption in the homeostasis of the vitamin D synthesis pathway in Mecp2+/− mice, and motor and anxiety-like behavioral phenotypes in Mecp2+/− mice correlate with circulating vitamin D levels. Thus, our data indicate that vitamin D modulates RTT pathology and its supplementation could provide a simple and cost-effective partial therapeutic for RTT.

MECP2 Mutations in the Rett Syndrome Patients from South India.

Rett syndrome (RTT) is a rare neurological disorder that primarily affects the females. Most cases of RTT are caused by a de novo mutation in the MECP2 gene located on the X chromosome. About 1000 MECP2 mutations have been found to be associated with RTT. The present study is aimed at the mutation screening of MECP2 gene in the RTT patients belonging to the south Indian state of Kerala. In total 22 girls with a clinical suspicion of RTT were recruited for the study. Exons 2, 3, and 4 of MECP2 were amplified and sequenced. MECP2 mutations were observed in 12 patients. While 7 mutations were pathogenic, 4 were benign. All of the mutations were located in exons 3 and 4 of MECP2, spanning the methyl-CpG DNA binding domain (MBD), transcription repression domain (TRD), and C-terminal domain (CTD) domains of the MECP2 protein. Four novel mutations were identified. There were no mutations in the MECP2 gene of 10 patients with a clinical suspicion of RTT. A recommended screening strategy for RTT is to first look for mutations in exons 3 and 4 of MECP2, followed by exons 1 and 2, testing for large deletions in MECP2, and screening for mutations in genes, such as CDKL5 and FOXG1 that are reported to cause a Rett-like phenotype.

JNK signaling provides a novel therapeutic target for Rett syndrome

BackgroundRett syndrome (RTT) is a monogenic X-linked neurodevelopmental disorder characterized by loss-of-function mutations in the MECP2 gene, which lead to structural and functional changes in synapse communication, and impairments of neural activity at the basis of cognitive deficits that progress from an early age. While the restoration of MECP2 in animal models has been shown to rescue some RTT symptoms, gene therapy intervention presents potential side effects, and with gene- and RNA-editing approaches still far from clinical application, strategies focusing on signaling pathways downstream of MeCP2 may provide alternatives for the development of more effective therapies in vivo. Here, we investigate the role of the c-Jun N-terminal kinase (JNK) stress pathway in the pathogenesis of RTT using different animal and cell models and evaluate JNK inhibition as a potential therapeutic approach.ResultsWe discovered that the c-Jun N-terminal kinase (JNK) stress pathway is activated in Mecp2-knockout, Mecp2-heterozygous mice, and in human MECP2-mutated iPSC neurons. The specific JNK inhibitor, D-JNKI1, promotes recovery of body weight and locomotor impairments in two mouse models of RTT and rescues their dendritic spine alterations. Mecp2-knockout presents intermittent crises of apnea/hypopnea, one of the most invalidating RTT pathological symptoms, and D-JNKI1 powerfully reduces this breathing dysfunction. Importantly, we discovered that also neurons derived from hiPSC-MECP2 mut show JNK activation, high-phosphorylated c-Jun levels, and cell death, which is not observed in the isogenic control wt allele hiPSCs. Treatment with D-JNKI1 inhibits neuronal death induced by MECP2 mutation in hiPSCs mut neurons.ConclusionsAs a summary, we found altered JNK signaling in models of RTT and suggest that D-JNKI1 treatment prevents clinical symptoms, with coherent results at the cellular, molecular, and functional levels. This is the first proof of concept that JNK plays a key role in RTT and its specific inhibition offers a new and potential therapeutic tool to tackle RTT.

Sex disparate gut microbiome and metabolome perturbations precede disease progression in a mouse model of Rett syndrome

Rett syndrome (RTT) is a regressive neurodevelopmental disorder in girls, characterized by multisystem complications including gut dysbiosis and altered metabolism. While RTT is known to be caused by mutations in the X-linked gene MECP2, the intermediate molecular pathways of progressive disease phenotypes are unknown. Mecp2 deficient rodents used to model RTT pathophysiology in most prior studies have been male. Thus, we utilized a patient-relevant mouse model of RTT to longitudinally profile the gut microbiome and metabolome across disease progression in both sexes. Fecal metabolites were altered in Mecp2e1 mutant females before onset of neuromotor phenotypes and correlated with lipid deficiencies in brain, results not observed in males. Females also displayed altered gut microbial communities and an inflammatory profile that were more consistent with RTT patients than males. These findings identify new molecular pathways of RTT disease progression and demonstrate the relevance of further study in female Mecp2 animal models.

Substantial acetylcholine reduction in multiple brain regions of Mecp2-deficient female rats and associated behavioral abnormalities.

Rett syndrome (RTT) is a neurodevelopmental disorder with X-linked dominant inheritance caused mainly by mutations in the methyl-CpG-binding protein 2 (MECP2) gene. The effects of various Mecp2 mutations have been extensively assessed in mouse models, but none adequately mimic the symptoms and pathological changes of RTT. In this study, we assessed the effects of Mecp2 gene deletion on female rats (Mecp2+/-) and found severe impairments in social behavior [at 8 weeks (w), 12 w, and 23 w of age], motor function [at 16 w and 26 w], and spatial cognition [at 29 w] as well as lower plasma insulin-like growth factor (but not brain-derived neurotrophic factor) and markedly reduced acetylcholine (30%-50%) in multiple brain regions compared to female Mecp2+/+ rats [at 29 w]. Alternatively, changes in brain monoamine levels were relatively small, in contrast to reports on mouse Mecp2 mutants. Female Mecp2-deficient rats express phenotypes resembling RTT and so may provide a robust model for future research on RTT pathobiology and treatment.

Pre-clinical Investigation of Rett Syndrome Using Human Stem Cell-Based Disease Models.

Rett syndrome (RTT) is an X-linked neurodevelopmental disorder, mostly caused by mutations in MECP2. The disorder mainly affects girls and it is associated with severe cognitive and physical disabilities. Modeling RTT in neural and glial cell cultures and brain organoids derived from patient- or mutation-specific human induced pluripotent stem cells (iPSCs) has advanced our understanding of the pathogenesis of RTT, such as disease-causing mechanisms, disease progression, and cellular and molecular pathology enabling the identification of actionable therapeutic targets. Brain organoid models that recapitulate much of the tissue architecture and the complexity of cell types in the developing brain, offer further unprecedented opportunity for elucidating human neural development, without resorting to conventional animal models and the limited resource of human neural tissues. This review focuses on the new knowledge of RTT that has been gleaned from the iPSC-based models as well as limitations of the models and strategies to refine organoid technology in the quest for clinically relevant disease models for RTT and the broader spectrum of neurodevelopmental disorders.

MeCP2 is a microsatellite binding protein that protects CA repeats from nucleosome invasion.

The Rett syndrome protein MeCP2 was described as a methyl-CpG-binding protein, but its exact function remains unknown. Here we show that mouse MeCP2 is a microsatellite binding protein that specifically recognizes hydroxymethylated CA repeats. Depletion of MeCP2 alters chromatin organization of CA repeats and lamina-associated domains and results in nucleosome accumulation on CA repeats and genome-wide transcriptional dysregulation. The structure of MeCP2 in complex with a hydroxymethylated CA repeat reveals a characteristic DNA shape, with considerably modified geometry at the 5-hydroxymethylcytosine, which is recognized specifically by Arg133, a key residue whose mutation causes Rett syndrome. Our work identifies MeCP2 as a microsatellite DNA binding protein that targets the 5hmC-modified CA-rich strand and maintains genome regions nucleosome-free, suggesting a role for MeCP2 dysfunction in Rett syndrome.

Treatment with the Bacterial Toxin CNF1 Selectively Rescues Cognitive and Brain Mitochondrial Deficits in a Female Mouse Model of Rett Syndrome Carrying a MeCP2-Null Mutation.

Rett syndrome (RTT) is a rare neurological disorder caused by mutations in the X-linked MECP2 gene and a major cause of intellectual disability in females. No cure exists for RTT. We previously reported that the behavioural phenotype and brain mitochondria dysfunction are widely rescued by a single intracerebroventricular injection of the bacterial toxin CNF1 in a RTT mouse model carrying a truncating mutation of the MeCP2 gene (MeCP2-308 mice). Given the heterogeneity of MECP2 mutations in RTT patients, we tested the CNF1 therapeutic efficacy in a mouse model carrying a null mutation (MeCP2-Bird mice). CNF1 selectively rescued cognitive defects, without improving other RTT-related behavioural alterations, and restored brain mitochondrial respiratory chain complex activity in MeCP2-Bird mice. To shed light on the molecular mechanisms underlying the differential CNF1 effects on the behavioural phenotype, we compared treatment effects on relevant signalling cascades in the brain of the two RTT models. CNF1 provided a significant boost of the mTOR activation in MeCP2-308 hippocampus, which was not observed in the MeCP2-Bird model, possibly explaining the differential effects of CNF1. These results demonstrate that CNF1 efficacy depends on the mutation beared by MeCP2-mutated mice, stressing the need of testing potential therapeutic approaches across RTT models.

Altered Bone Status in Rett Syndrome.

Rett syndrome (RTT) is a monogenic neurodevelopmental disorder primarily caused by mutations in X-linked MECP2 gene, encoding for methyl-CpG binding protein 2 (MeCP2), a multifaceted modulator of gene expression and chromatin organization. Based on the type of mutation, RTT patients exhibit a broad spectrum of clinical phenotypes with various degrees of severity. In addition, as a complex multisystem disease, RTT shows several clinical manifestations ranging from neurological to non-neurological symptoms. The most common non-neurological comorbidities include, among others, orthopedic complications, mainly scoliosis but also early osteopenia/osteoporosis and a high frequency of fractures. A characteristic low bone mineral density dependent on a slow rate of bone formation due to dysfunctional osteoblast activity rather than an increase in bone resorption is at the root of these complications. Evidence from human and animal studies supports the idea that MECP2 mutation could be associated with altered epigenetic regulation of bone-related factors and signaling pathways, including SFRP4/WNT/β-catenin axis and RANKL/RANK/OPG system. More research is needed to better understand the role of MeCP2 in bone homeostasis. Indeed, uncovering the molecular mechanisms underlying RTT bone problems could reveal new potential pharmacological targets for the treatment of these complications that adversely affect the quality of life of RTT patients for whom the only therapeutic approaches currently available include bisphosphonates, dietary supplements, and physical activity.

MeCP2 deficiency exacerbates the neuroinflammatory setting and autoreactive response during an autoimmune challenge

Rett syndrome is a severe and progressive neurological disorder linked to mutations in the MeCP2 gene. It has been suggested that immune alterations may play an active role in the generation and/or maintenance of RTT phenotypes. However, there is no clear consensus about which pathways are regulated in vivo by MeCP2 in the context of immune activation. In the present work we set to characterize the role of MeCP2 during the progression of Experimental Autoimmune Encephalomyelitis (EAE) using the MeCP2308/y mouse model (MUT), which represents a condition of “MeCP2 function deficiency”. Our results showed that MeCP2 deficiency increased the susceptibility to develop EAE, along with a defective induction of anti-inflammatory responses and an exacerbated MOG-specific IFNγ expression in immune sites. In MUT-EAE spinal cord, we found a chronic increase in pro-inflammatory cytokines gene expression (IFNγ, TNFα and IL-1β) and downregulation of genes involved in immune regulation (IL-10, FoxP3 and CX3CR1). Moreover, our results indicate that MeCP2 acts intrinsically upon immune activation, affecting neuroimmune homeostasis by regulating the pro-inflammatory/anti-inflammatory balance in vivo. These results are relevant to identify the potential consequences of MeCP2 mutations on immune homeostasis and to explore novel therapeutic strategies for MeCP2-related disorders.

Safety and efficacy of genetic MECP2 supplementation in the R294X mouse model of Rett syndrome.

Rett syndrome is a neurodevelopmental disorder caused predominantly by loss-of-function mutations in MECP2, encoding transcriptional modulator methyl-CpG-binding protein 2 (MeCP2). Although no disease-modifying therapies exist at this time, some proposed therapeutic strategies aim to supplement the mutant allele with a wild-type allele producing typical levels of functional MeCP2, such as gene therapy. Because MECP2 is a dosage-sensitive gene, with both loss and gain of function causing disease, these approaches must achieve a narrow therapeutic window to be both safe and effective. While MeCP2 supplementation rescues RTT-like phenotypes in mouse models, the tolerable threshold of MeCP2 is not clear, particularly for partial loss-of-function mutations. We assessed the safety of genetically supplementing full-length human MeCP2 in the context of the R294X allele, a common partial loss-of-function mutation retaining DNA-binding capacity. We assessed the potential for adverse effects from MeCP2 supplementation of a partial loss-of-function mutant and the potential for dominant negative interactions between mutant and full-length MeCP2. In male hemizygous R294X mice, MeCP2 supplementation rescued RTT-like behavioral phenotypes and did not elicit behavioral evidence of excess MeCP2. In female heterozygous R294X mice, RTT-specific phenotypes were similarly rescued. However, MeCP2 supplementation led to evidence of excess MeCP2 activity in a motor coordination assay, suggesting that the underlying motor circuitry is particularly sensitive to MeCP2 dosage in females. These results show that genetic supplementation of full-length MeCP2 is safe in males and largely so females. However, careful consideration of risk for adverse motor effects may be warranted for girls and women with RTT.

MeCP2 controls neural stem cell fate specification through miR-199a-mediated inhibition of BMP-Smad signaling.

Rett syndrome (RTT) is a severe neurological disorder, with impaired brain development caused by mutations in MECP2; however, the underlying mechanism remains elusive. We know from previous work that MeCP2 facilitates the processing of a specific microRNA, miR-199a, by associating with the Drosha complex to regulate neuronal functions. Here, we show that the MeCP2/miR-199a axis regulates neural stem/precursor cell (NS/PC) differentiation. A shift occurs from neuronal to astrocytic differentiation of MeCP2- and miR-199a-deficient NS/PCs due to the upregulation of a miR-199a target, Smad1, a downstream transcription factor of bone morphogenetic protein (BMP) signaling. Moreover, miR-199a expression and treatment with BMP inhibitors rectify the differentiation of RTT patient-derived NS/PCs and development of brain organoids, respectively, suggesting that facilitation of BMP signaling accounts for the impaired RTT brain development. Our study illuminates the molecular pathology of RTT and reveals the MeCP2/miR-199a/Smad1 axis as a potential therapeutic target for RTT.

MECP2-Related Disorders and Epilepsy Phenotypes

Abstract MECP2 (methyl-CpG binding protein-2) gene, located on chromosome Xq28, encodes for a protein particularly abundant in the brain that is required for maturation of astrocytes and neurons and is developmentally regulated. A defective homeostasis of MECP2 expression, either by haploinsufficiency or overexpression, leads to a neurodevelopmental phenotype. As MECP2 is located on chromosome X, the clinical presentation varies in males and females ranging from mild learning disabilities to severe encephalopathies and early death. Typical Rett syndrome (RTT), the most frequent phenotype associated with MECP2 mutations, primarily affects girls and it was previously thought to be lethal in males; however, MECP2 duplication syndrome, resulting from a duplication of the Xq28 region including MECP2, leads to a severe neurodevelopmental disorder in males. RTT and MECP2 duplication syndrome share overlapping clinical phenotypes including intellectual disabilities, motor deficits, hypotonia, progressive spasticity, and epilepsy. In this manuscript we reviewed literature on epilepsy related to MECP2 disorders, focusing on clinical presentation, genotype–phenotype correlation, and treatment.

Dietary intake and growth deficits in Rett syndrome—A cross‐section study

Growth deficit is a common comorbidity and one of the supportive criteria in Rett syndrome (RTT). This study aimed to investigate the impact of dystonia, dietary intakes, and clinical severities on growth patterns in a Taiwanese cohort of RTT. We recruited 44 RTT patients with MECP2 mutation for analysis. For individuals ≤18 years of age, in comparison to the RTT-specific growth chart which comprised American RTT cohort, the body height was right-shifted to a higher percentile, whereas the body weight was left-shifted to a lower percentile. Furthermore, the body mass index was significantly decreased when compared to RTT-specific growth chart (p = 0.01). Higher degree of overall disease severity (odd ratio = 1.159; 95% CI = 1.063-1.264; p = 0.001) and hand use impairment (odd ratio = 2.017; 95% CI = 1.037, 3.921; p = 0.039) were associated with more severe growth patterns. All individuals had dystonia at certain variable degrees. The dystonia worsened with age (p < 0.001) but did not have significant impact on growth deficit. Most of our cohort had adequate protein (97.37%) and energy (58.97%) intakes. The fiber intakes were generally low, with about 38 (97.4%) individuals did not meet the daily reference intakes of fiber. The protein intake was significantly lower in individuals with severe growth deficit (p = 0.04). Our study shows that ethnicity should be considered when comparing RTT individuals' growth pattern to the RTT-specific growth chart. Further, disease severity, genotypes, and nutrition exert important impacts on RTT-growth pattern. LAY SUMMARY: Growth impairment is an important issue in Rett syndrome and the underlying patho-mechanism is multifactorial. Higher degree of overall disease severity and hand use impairment were associated with more severe growth pattern deficits. Although all individuals had dystonia at certain variable degrees and the dystonia worsened with age, but it did not have significant impact on growth deficit. Nutritional intakes may partially affect growth. Furthermore, ethnicity should be considered when comparing RTT individuals' growth pattern to the RTT-specific growth chart.

Presymptomatic training mitigates functional deficits in a mouse model of Rett syndrome.

Mutations in the X-linked gene MECP2 cause Rett syndrome, a progressive neurological disorder in which children develop normally for the first one or two years of life before experiencing profound motor and cognitive decline1-3. At present there are no effective treatments for Rett syndrome, but we hypothesized that using the period of normal development to strengthen motor and memory skills might confer some benefit. Here we find, using a mouse model of Rett syndrome, that intensive training beginning in the presymptomatic period dramatically improves the performance of specific motor and memory tasks, and significantly delays the onset of symptoms. These benefits are not observed when the training begins after symptom onset. Markers of neuronal activity and chemogenetic manipulation reveal that task-specific neurons that are repeatedly activated during training develop more dendritic arbors and have better neurophysiological responses than those in untrained animals, thereby enhancing their functionality and delaying symptom onset. These results provide a rationale for genetic screening of newborns for Rett syndrome, as presymptomatic intervention might mitigate symptoms or delay their onset. Similar strategies should be studied for other childhood neurological disorders.

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

MECP2 mutations cause Rett syndrome (RTT), a severe and progressive neurodevelopmental disorder mainly affecting females. Although RTT patients exhibit delayed onset of symptoms, several evidences demonstrate that MeCP2 deficiency alters early development of the brain. Indeed, during early maturation, Mecp2 null cortical neurons display widespread transcriptional changes, reduced activity, and defective morphology. It has been proposed that during brain development these elements are linked in a feed‐forward cycle where neuronal activity drives transcriptional and morphological changes that further increase network maturity. We hypothesized that the enhancement of neuronal activity during early maturation might prevent the onset of RTT‐typical molecular and cellular phenotypes. Accordingly, we show that the enhancement of excitability, obtained by adding to neuronal cultures Ampakine CX546, rescues transcription of several genes, neuronal morphology, and responsiveness to stimuli. Greater effects are achieved in response to earlier treatments. In vivo, short and early administration of CX546 to Mecp2 null mice prolongs lifespan, delays the disease progression, and rescues motor abilities and spatial memory, thus confirming the value for RTT of an early restoration of neuronal activity.

Loss of MeCP2 causes subtle alteration in dendritic arborization of retinal ganglion cells

ABSTRACT Methyl-CpG-binding protein (MeCP2) is highly expressed in neurons. It plays an important role in the development of synapses and the formation of circuits in the central nervous system (CNS). Mutations in MECP2 cause neurodevelopmental disorders and mental retardation in humans. Therefore, it has become important to determine the distribution and function of MeCP2 in vivo. The retina consists of three nuclear cell layers and two layers of synapses; neurons in each layer are connected to form fine circuits necessary for visual signal transduction. Using immunohistochemical analysis, we found that MeCP2 was expressed in all nuclear cell layers, with differences in the levels of MeCP2 expression observed among the layers. To understand the structural defects in the retina due to the loss of MeCP2, we sought to elucidate the organization of the retinal structure in the Mecp2 knockout (KO) mouse. Overall, we found a normal retinal structure in Mecp2 KO mice. However, because Mecp2 mutations have a highly variable effect on neuronal architecture, we analyzed morphological changes in a subset of retinal ganglion cells of Mecp2 KO mice. In Thy1-GFP mice crossed with Mecp2 mutant mice, Sholl intersections analyses showed a subtle increase in number of intersections due to increased branching proximal to the soma in Mecp2 KO mice. Our results demonstrate that the expression of MeCP2 and the effects of Mecp2 mutations are highly specific to tissue and cell types.

Stimulation of the Serotonin Receptor 7 Restores Brain Histone H3 Acetylation and MeCP2 Corepressor Protein Levels in a Female Mouse Model of Rett Syndrome

Rett syndrome (RTT) is a rare neurological disorder caused by mutations in the X-linked MECP2 gene, characterized by severe behavioral and physiological impairments for which no cure is available. The stimulation of serotonin receptor 7 (5-HT7R) with its selective agonist LP-211 (0.25 mg/kg/day for 7 days) was proved to rescue neurobehavioral alterations in a mouse model of RTT. In the present study, we aimed at gaining insight into the mechanisms underpinning the efficacy of 5-HT7R pharmacological stimulation by investigating its epigenetic outcomes in the brain of RTT female mice bearing a truncating MeCP2 mutation. Treatment with LP-211 normalized the reduced histone H3 acetylation and HDAC3/NCoR levels, and increased HDAC1/Sin3a expression in RTT mouse cortex. Repeated 5-HT7R stimulation also appeared to strengthen the association between NCoR and MeCP2 in the same brain region. A different profile was found in RTT hippocampus, where LP-211 rescued H3 hyperacetylation and increased HDAC3 levels. Overall, the present data highlight a new scenario on the relationship between histone acetylation and serotoninergic pathways. 5-HT7R is confirmed as a pivotal therapeutic target for the recovery of neuronal function supporting the translational value of this promising pharmacological approach for RTT.