MECP2 Research Articles

LEDGF interacts with the NID domain of MeCP2 and modulates MeCP2 condensates.

Methyl-CpG-binding protein 2 (MeCP2) is a ubiquitously expressed nuclear protein involved in transcriptional regulation and chromatin remodeling. MeCP2 exists in two isoforms, MeCP2 E1 and E2, which share the same functional domains. Loss-of-function mutations in the MeCP2 gene are the main cause of Rett syndrome (RTT). Previous studies identified a complex formation between MeCP2 and lens epithelium derived growth factor (LEDGF), a transcriptional regulator that exists in two isoforms, LEDGF/p75 and LEDGF/p52. Here, we characterized the molecular and functional interaction between MeCP2 and LEDGF. The NCoR interaction domain (NID) domain in MeCP2 is essential for the direct binding to the PWWP-CR1 region of LEDGF. Introduction of R306C, an RTT mutation in the NID of MeCP2, reduced the interaction with LEDGF. Our data reveal mutual inhibition of MeCP2 and LEDGF multimerization due to overlapping binding sites. Aligning with this observation, LEDGF depletion resulted in larger MeCP2 and DNA foci in NIH3T3 cells, suggesting a role for the MeCP2-LEDGF complex in chromatin organization.

GM1 Oligosaccharide Ameliorates Rett Syndrome Phenotypes In Vitro and In Vivo via Trk Receptor Activation

Rett syndrome (RTT) is a severe neurodevelopmental disorder primarily caused by mutations in the methyl-CpG binding protein 2 (MECP2) gene. Despite advancements in research, no cure exists due to an incomplete understanding of the molecular effects of MeCP2 deficiency. Previous studies have identified impaired tropomyosin receptor kinase (Trk) neurotrophin (NTP) signaling and mitochondrial redox imbalances as key drivers of the pathology. Moreover, altered glycosphingolipid metabolism has been reported in RTT. GM1 ganglioside is a known regulator of the nervous system, and growing evidence indicates its importance in maintaining neuronal homeostasis via its oligosaccharide chain, coded as GM1-OS. GM1-OS directly interacts with the Trk receptors on the cell surface, triggering neurotrophic and neuroprotective pathways in neurons. In this study, we demonstrate that GM1-OS ameliorates RTT deficits in the Mecp2-null model. GM1-OS restored synaptogenesis and reduced mitochondrial oxidative stress of Mecp2-knock-out (ko) cortical neurons. When administered in vivo, GM1-OS mitigated RTT-like symptoms. Our findings indicate that GM1-OS effects were mediated by Trk receptor activation on the neuron’s plasma membrane. Overall, our results highlight GM1-OS as a promising candidate for RTT treatment.

The Expression of Cytokines and Chemokines Potentially Distinguishes Mild and Severe Psoriatic Non-Lesional and Resolved Skin from Healthy Skin and Indicates Different Stages of Inflammation

In the psoriatic non-lesional (PS-NL) skin, the tissue environment potentially influences the development and recurrence of lesions. Therefore, we aimed to investigate mechanisms involved in regulating tissue organization in PS-NL skin. Cytokine, chemokine, protease, and protease inhibitor levels were compared between PS-NL skin of patients with mild and severe symptoms and healthy skin. By comparing mild and severe PS-NL vs. healthy skin, differentially expressed cytokines and chemokines suggested alterations in hemostasis-related processes, while protease inhibitors showed no psoriasis severity-related changes. Comparing severe and mild PS-NL skin revealed disease severity-related changes in the expression of proteases, cytokines, and chemokines primarily involving methyl-CpG binding protein 2 (MECP2) and extracellular matrix organization-related mechanisms. Cytokine and chemokine expression in clinically resolved versus healthy skin showed slight interleukin activity, differing from patterns in mild and severe PS-NL skin. Immunofluorescence analysis revealed the severity-dependent nuclear expression pattern of MECP2 and decreased expression of 5-methylcytosine and 5-hydroxymethylcytosine in the PS-NL vs. healthy skin, and in resolved vs. healthy skin. Our results suggest distinct cytokine–chemokine signaling between the resolved and PS-NL skin of untreated patients with varying severities. These results highlight an altered inflammatory response, epigenetic regulation, and tissue organization in different types of PS-NL skin with possibly distinct, severity-dependent para-inflammatory states.

RettDb: the Rett syndrome omics database to navigate the Rett syndrome genomic landscape.

Rett syndrome (RTT) is a neurodevelopmental disorder occurring almost exclusively in females and leading to a variety of impairments and disabilities from mild to severe. In >95% cases, RTT is due to mutations in the X-linked gene MECP2, but the molecular mechanisms determining RTT are unknown at present, and the complexity of the system is challenging. To facilitate and provide guidance to the unraveling of those mechanisms, we developed a database resource for the visualization and analysis of the genomic landscape in the context of wild-type or mutated Mecp2 gene in the mouse model. Our resource allows for the exploration of differential dynamics of gene expression and the prediction of new potential MECP2 target genes to decipher the RTT disorder molecular mechanisms. Database URL: https://biomedinfo.di.unipi.it/rett-database/.

Site-Blocking Antisense Oligonucleotides as a Mechanism to Fine-Tune MECP2 Expression.

Rett syndrome (RTT) is a neurodevelopmental disorder caused by loss-of-function mutations in the methyl CpG binding protein 2 (MECP2) gene. Despite its severe phenotype, studies in mouse models suggest that restoring MeCP2 levels can reverse RTT symptomology. Nevertheless, traditional gene therapy approaches are hindered by MECP2's narrow therapeutic window, complicating the safe delivery of viral constructs without overshooting the threshold for toxicity. The 3' untranslated region (3'UTR) plays a key role in gene regulation, where factors like miRNAs bind to pre-mRNA and fine-tune expression. Given that each miRNA's contribution is modest, blocking miRNA binding may represent a potential therapeutic strategy for diseases with high dosage sensitivity, like RTT. Here, we present a series of site-blocking antisense oligonucleotides (sbASOs) designed to outcompete repressive miRNA binding at the MECP2 3'UTR. This strategy aims to increase MECP2 levels in patients with missense or late-truncating mutations, where the hypomorphic nature of the protein can be offset by increased abundance. Our results demonstrate that sbASOs can elevate MECP2 levels in a dose-dependent manner in SH-SY5Y and patient fibroblast cell lines, plateauing at levels projected to be safe. Confirming in vivo functionality, sbASO administration in wild-type mice led to significant MeCP2 upregulation and the emergence of phenotypes associated with MeCP2 overexpression. In a T158M neural stem cell model of RTT, sbASO treatment significantly increased MECP2 expression and levels of the downstream effector protein, brain-derived neurotrophic factor (BDNF). These findings highlight the potential of sbASO-based therapies for MECP2-related disorders and advocate for their continued development.

USP15 inhibits hypoxia-induced IL-6 signaling by deubiquitinating and stabilizing MeCP2.

Methyl-CpG binding protein 2 (MeCP2) is an important X-linked DNA methylation reader and a key heterochromatin organizer. The expression level of MeCP2 is crucial, as indicated by the observation that loss-of-function mutations of MECP2 cause Rett syndrome, whereas an extra copy spanning the MECP2 locus results in MECP2 duplication syndrome, both being progressive neurodevelopmental disorders. Our previous study demonstrated that MeCP2 protein expression is rapidly induced by renal ischemia-reperfusion injury (IRI) and protects the kidney from IRI through transcriptionally repressing the interleukin-6 (IL-6)/signal transducer and activator of transcription 3 signaling pathway. However, the mechanisms underlying the upregulation of MeCP2 have remained elusive. Here, by using two hypoxia cell models, hypoxia and reoxygenation and cobalt chloride stimulation, we confirmed that the removal of lysine 48-linked ubiquitination from MeCP2 prevented its proteasome-dependent degradation under hypoxic conditions. Through unbiased screening based on a deubiquitinating enzymes library, we identified ubiquitin-specific protease 15 (USP15) as a stabilizer of MeCP2. Further studies revealed that USP15 could attenuate hypoxia-induced MeCP2 degradation by cleaving lysine 48-linked ubiquitin chains from MeCP2, primarily targeting its C-terminal domain. Consistently, USP15 inhibited hypoxia-induced signal transducer and activator of transcription 3 activation, resulting in reduced transcription of IL-6 downstream genes. In summary, our study reveals an important role for USP15 in the maintenance of MeCP2 stability and the regulation of IL-6 signaling.

8428 Rare Variants in the MECP2 Gene in Two Boys with Central Precocious Puberty

Abstract Disclosure: A.P. Canton: None. J.B. Mebarak: None. M. Magnuson: None. S. Roberts: None. N. Mauras: None. M. Benson: None. S. Witchel: None. R.S. Carroll: None. A. Latronico: None. U.B. Kaiser: None. A. Abreu: None. Introduction: Central precocious puberty (CPP) occurs more frequently in girls and is usually labelled as idiopathic; however, in boys organic causes are more frequent. Identification of imprinted genes causing CPP have revealed epigenetic mechanisms underlying puberty. MECP2, an X-linked gene, encodes a methylated DNA reader protein with a role in gene transcription. MECP2 loss-of-function mutations usually cause Rett syndrome, a severe neurodevelopmental disorder that may be associated with early pubertal development. Recently, rare variants in MECP2 have been recognized in girls with sporadic CPP with or without mild neurodevelopmental disorders. In our cohort of 78 patients with idiopathic CPP, no MECP2 mutations were identified in 73 girls. In this study, five boys with CPP were evaluated for potential MECP2 sequence variants. Methods and Results: Five boys with CPP were screened for MECP2 sequence variants using Sanger sequencing. At the time of CPP diagnosis, they had median (interquartile range) chronological age 9.2 yr (4.3), bone age advancement 2.1 yr (3.5), height SDS 2.3 (1.5), basal LH levels 1.6 IU/L (0.9), and testosterone levels 370 ng/dL (570). Organic causes of CPP were excluded. No MKRN3 or DLK1 mutations were identified. Familial segregation analysis was performed when appropriate. We identified a hemizygous MECP2 variant in a boy (Patient 1) who presented at age 2.7 yr with sporadic CPP. In addition, he had speech delay and behavioral changes, defined as autism spectrum disorder by neuropsychological assessment. He harbored an extremely rare (gnomAD AF=0.000004956) missense variant (p.Val312Ile) in exon 3 of MECP2, encoding the transcriptional repression domain, critical for protein function. The p.Val312Ile mutation was classified as likely pathogenic (ACMG criteria) with a potential association with the phenotype. Another hemizygous MECP2 variant was identified in a boy (Patient 2) who presented at age 8.0 yr with sporadic CPP; he had no neurodevelopmental conditions. He harbored a rare (gnomAD AF=0.00008) missense variant (p.Arg366Cys) in exon 3, encoding the C-terminal domain, classified as a variant of uncertain significance (ACMG criteria). Familial segregation analysis revealed that both boys inherited the MECP2 variants from their unaffected mothers, consistent with a pattern of clinical variability described in women with defects in X-linked genes.Conclusions: We identified rare MECP2 variants in two boys with sporadic CPP without classic features of Rett syndrome, expanding the phenotype of patients with MECP2 mutations, as described in girls. The MECP2 p.Val312Ile variant was likely pathogenic, whereas the functional significance of the p.Arg366Cys variant in still indeterminate. These findings provide additional evidence for a role of MECP2, an epigenetic factor, in the hypothalamic control of pubertal timing. Presentation: 6/1/2024

LRP1 Repression by SNAIL Results in ECM Remodeling in Genetic Risk for Vascular Diseases.

Genome-wide association studies implicate common genetic variations in the LRP1 (low-density lipoprotein receptor-related protein 1) locus at risk for multiple vascular diseases and traits. However, the underlying biological mechanisms are unknown. Fine mapping analyses included Bayesian colocalization to identify the most likely causal variant. Human induced pluripotent stem cells were genome-edited using CRISPR-Cas9 to delete or modify candidate enhancer regions and generate LRP1 knockout cell lines. Cells were differentiated into smooth muscle cells through a mesodermal lineage. Transcription regulation was assessed using luciferase reporter assay, transcription factor knockdown, and chromatin immunoprecipitation. Phenotype changes in cells were conducted using cellular assays, bulk RNA sequencing, and mass spectrometry. Multitrait colocalization analyses pointed at rs11172113 as the most likely causal variant in LRP1 for fibromuscular dysplasia, migraine, pulse pressure, and pulmonary function trait. We found the rs11172113-T allele to associate with higher LRP1 expression. Genomic deletion in induced pluripotent stem cell-derived smooth muscle cells supported rs11172113 to locate in an enhancer region regulating LRP1 expression. We found transcription factors MECP2 (methyl CpG binding protein 2) and SNAIL to repress LRP1 expression through an allele-specific mechanism, involving SNAIL interaction with disease risk allele. LRP1 knockout decreased induced pluripotent stem cell-derived smooth muscle cell proliferation and migration. Differentially expressed genes were enriched for collagen-containing extracellular matrix, connective tissue development, and lung development. LRP1 knockout and deletion of rs11172113 enhancer showed potentiated canonical TGF-β (transforming growth factor beta) signaling through enhanced phosphorylation of SMAD2/3. Analyses of the protein content of decellularized extracts indicated partial extracellular matrix remodeling involving enhanced secretion of CYR61, a known LRP1 ligand involved in vascular integrity and TIMP3, implicated in extracellular matrix maintenance and also known to interact with LRP1. Our findings support allele-specific LRP1 gene repression by the endothelial-to-mesenchymal transition regulator SNAIL. We propose decreased LRP1 expression in smooth muscle cells to remodel the extracellular matrix enhanced by TGF-β as a potential mechanism of this pleiotropic locus for vascular diseases.

Stress enhances aggression in male rats with genetic stress hyper-reactivity.

The current study investigated stress-induced aggressive behavior in the resident-intruder test in males of the genetically stress hyper-reactive Wistar Kyoto More Immobile (WMI), and the nearly isogenic, control Wistar Kyoto Less Immobile (WLI) strains. Tests were carried out against same-age intruders during adolescence, and same-age and juvenile intruders in adulthood. In adolescence and adulthood, prior acute restraint stress decreased social interactions and decreased aggressive behaviors of adolescents and adult WLIs. However, prior stress precipitated aggression in the adult WMI males toward both same-age, and juvenile intruders compared with control WMIs and WLIs. Trunk blood levels of testosterone and androstenedione increased in stressed WLIs, but not in WMIs, suggesting no direct role of androgens in the increased aggression of WMIs. Expressions of aggression-relevant genes showed patterns commensurate with being causative in aggressive behavior. The methyl-CpG binding protein 2 was lower in the frontal cortex of control WMIs, and in the amygdala of stressed WMIs compared with their respective WLIs. Frontal cortex expression of vasopressin receptor 1a and serotonin transporter increased, solely in WMI males after stress. As behaviors were the same toward same-age and non-threatening juvenile intruders, the stress-induced increase in confrontational behavior of the adult WMI male was not because of enhanced fear or anxiety. These results suggest that genetic stress hyper-reactivity is a risk factor for stress-induced increases in aggression in males. Additionally, as known aggression-related genes showed expression patterns paralleling aggressive behavior, this model system could identify novel molecular pathways leading to stress-enhanced aggression.

MeCP2 is a naturally supercharged protein with cell membrane transduction capabilities.

The intrinsically disordered protein MeCP2 is a global transcriptional regulator encoded by the MECP2 gene. Although the structured domains of MeCP2 have been the subject of multiple studies, its unstructured regions have not been that extensively characterized. In this work, we show that MeCP2 possesses properties akin to those of supercharged proteins. By utilizing its unstructured portions, MeCP2 can successfully transduce across cell membranes and localize to heterochromatic foci in the nuclei, displaying uptake levels a third lower than a MeCP2 construct fused to the cell-penetrating peptide TAT. MeCP2 uptake can further be enhanced by the addition of compounds that promote endosomal escape following cellular trafficking by means of macropinocytosis. Using a combination of in silico prediction algorithms and live-cell imaging experiments, we mapped the sequence in MeCP2 responsible for its cellular incorporation, which bears a striking resemblance to TAT itself. Transduced MeCP2 was shown to interact with HDAC3. These findings provide valuable insight into the properties of MeCP2 and may be beneficial for devising future protein-based treatment strategies.

Multi-gene duplication removal in an engineered human cellular MECP2 duplication syndrome model with an IRAK1-MECP2 duplication

Recent progress in genome editing technologies has catalyzed the generation of sophisticated cell models, however; the precise modeling of copy number variation (CNV) diseases remains a significant challenge, despite their substantial prevalence in the human population. To overcome this barrier, we have explored the utility of HAP1 cells for the accurate modeling of disease genomes with large structural variants. As an example, this study details the strategy to generate a novel cell line that serves as a model for the neurological disorder, MECP2 Duplication Syndrome (MDS), featuring the critical duplication of both the MECP2 and IRAK1 genes. This model faithfully recapitulates MDS genomic rearrangement, allowing for the mechanistic study of gene overexpression and the development of therapeutic interventions. Employing a single-guide RNA (sgRNA) CRISPR-Cas9 strategy, we successfully excised the duplicated genomic segment, notably halving both MECP2 and IRAK1 expression levels. The evidence establishes our model as a crucial tool for research into MDS. Furthermore, the outlined workflow is readily adaptable to model other CNV disorders and subsequently test genomic and pharmacological interventions.

Boosting Serotonin Synthesis Is Not Sufficient to Improve Motor Coordination of Mecp2 Heterozygous Mouse Model of Rett Syndrome.

Motor deficit is a core symptom of Rett syndrome, a rare neurological disease caused in most cases by mutations of the methyl-CpG-binding protein2 (MECP2) gene. Serotonin reuptake inhibitors improve motor coordination in Mecp2 heterozygous (Het) mice and serotonin depletion prevented this effect. Here, we assess alterations in indole levels in various brain regions and whether boosting brain serotonin synthesis with the serotonin precursors tryptophan, 5-hydroxytryptophan and α-lactalbumin rescued motor coordination deficit of Mecp2 Het mice. Motor coordination was assessed in the accelerated rotarod during and after systemic administration of serotonin precursors for 2-3 weeks. Since no data are available, the effect of α-lactalbumin on tryptophan, serotonin and 5-hydroxyindoleacetic acid levels was evaluated in various brain regions in order to identify the dose of ALAC to evaluate on motor coordination. As compared to WT, Mecp2 Het mice show reduced levels of serotonin in the whole brain, hippocampus, brainstem and cerebral cortex, but not the striatum. Reduced levels of 5-hydroxyindoleacetic acid were observed in the hippocampus and brainstem. Doses of serotonin precursors increasing brain tryptophan and/or serotonin production and metabolism had no effect on motor coordination. The results indicate that boosting serotonin synthesis is not sufficient to improve motor coordination of Mecp2 Het mice.

Involvement of extracellular vesicle microRNA clusters in developing healthy and Rett syndrome brain organoids

Rett syndrome (RTT) is a neurodevelopmental disorder caused by de novo mutations in the MECP2 gene. Although miRNAs in extracellular vesicles (EVs) have been suggested to play an essential role in several neurological conditions, no prior study has utilized brain organoids to profile EV-derived miRNAs during normal and RTT-affected neuronal development. Here we report the spatiotemporal expression pattern of EV-derived miRNAs in region-specific forebrain organoids generated from female hiPSCs with a MeCP2:R255X mutation and the corresponding isogenic control. EV miRNA and protein expression profiles were characterized at day 0, day 13, day 40, and day 75. Several members of the hsa-miR-302/367 cluster were identified as having a time-dependent expression profile with RTT-specific alterations at the latest developmental stage. Moreover, the miRNA species of the chromosome 14 miRNA cluster (C14MC) exhibited strong upregulation in RTT forebrain organoids irrespective of their spatiotemporal location. Together, our results suggest essential roles of the C14MC and hsa-miR-302/367 clusters in EVs during normal and RTT-associated neurodevelopment, displaying promising prospects as biomarkers for monitoring RTT progression.Graphical

Pharmacological inhibition of the CB1 cannabinoid receptor restores abnormal brain mitochondrial CB1 receptor expression and rescues bioenergetic and cognitive defects in a female mouse model of Rett syndrome

BackgroundDefective mitochondria and aberrant brain mitochondrial bioenergetics are consistent features in syndromic intellectual disability disorders, such as Rett syndrome (RTT), a rare neurologic disorder that severely affects mainly females carrying mutations in the X-linked MECP2 gene. A pool of CB1 cannabinoid receptors (CB1R), the primary receptor subtype of the endocannabinoid system in the brain, is located on brain mitochondrial membranes (mtCB1R), where it can locally regulate energy production, synaptic transmission and memory abilities through the inhibition of the intra-mitochondrial protein kinase A (mtPKA). In the present study, we asked whether an overactive mtCB1R-mtPKA signaling might underlie the brain mitochondrial alterations in RTT and whether its modulation by systemic administration of the CB1R inverse agonist rimonabant might improve bioenergetics and cognitive defects in mice modeling RTT.MethodsRimonabant (0.3 mg/kg/day, intraperitoneal injections) was administered daily to symptomatic female mice carrying a truncating mutation of the Mecp2 gene and its effects on brain mitochondria functionality, systemic oxidative status, and memory function were assessed.ResultsmtCB1R is overexpressed in the RTT mouse brain. Subchronic treatment with rimonabant normalizes mtCB1R expression in RTT mouse brains, boosts mtPKA signaling, and restores the defective brain mitochondrial bioenergetics, abnormal peripheral redox homeostasis, and impaired cognitive abilities in RTT mice.LimitationsThe lack of selectivity of the rimonabant treatment towards mtCB1R does not allow us to exclude that the beneficial effects exerted by the treatment in the RTT mouse model may be ascribed more broadly to the modulation of CB1R activity and distribution among intracellular compartments, rather than to a selective effect on mtCB1R-mediated signaling. The low sample size of few experiments is a further limitation that has been addressed replicating the main findings under different experimental conditions.ConclusionsThe present data identify mtCB1R overexpression as a novel molecular alteration in the RTT mouse brain that may underlie defective brain mitochondrial bioenergetics and cognitive dysfunction.

Modeling antisense oligonucleotide therapy in MECP2 duplication syndrome human iPSC-derived neurons reveals gene expression programs responsive to MeCP2 levels.

Genomic copy-number variations (CNVs) that can cause neurodevelopmental disorders often encompass many genes, which complicates our understanding of how individual genes within a CNV contribute to pathology. MECP2 duplication syndrome (MDS or MRXSL in OMIM; OMIM#300260) is one such CNV disorder caused by duplications spanning methyl CpG-binding protein 2 (MECP2) and other genes on Xq28. Using an antisense oligonucleotide (ASO) to normalize MECP2 dosage is sufficient to rescue abnormal neurological phenotypes in mouse models overexpressing MECP2 alone, implicating the importance of increased MECP2 dosage within CNVs of Xq28. However, because MDS CNVs span MECP2 and additional genes, we generated human neurons from multiple MDS patient-derived induced pluripotent cells (iPSCs) to evaluate the benefit of using an ASO against MECP2 in a MDS human neuronal context. Importantly, we identified a signature of genes that is partially and qualitatively modulated upon ASO treatment, pinpointed genes sensitive to MeCP2 function, and altered in a model of Rett syndrome, a neurological disorder caused by loss of MeCP2 function. Furthermore, the signature contained genes that are aberrantly altered in unaffected control human neurons upon MeCP2 depletion, revealing gene expression programs qualitatively sensitive to MeCP2 levels in human neurons. Lastly, ASO treatment led to a partial rescue of abnormal neuronal morphology in MDS neurons. All together, these data demonstrate that ASOs targeting MECP2 benefit human MDS neurons. Moreover, our study establishes a paradigm by which to evaluate the contribution of individual genes within a CNV to pathogenesis and to assess their potential as a therapeutic target.

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Elucidating the molecular symphony: unweaving the transcriptional & epigenetic pathways underlying neuroplasticity in opioid dependence and withdrawal.

The persistent use of opioids leads to profound changes in neuroplasticity of the brain, contributing to the emergence and persistence of addiction. However, chronic opioid use disrupts the delicate balance of the reward system in the brain, leading to neuroadaptations that underlie addiction. Chronic cocaine usage leads to synchronized alterations in gene expression, causing modifications in the Nucleus Accumbens (NAc), a vital part of the reward system of the brain. These modifications assist in the development of maladaptive behaviors that resemble addiction. Neuroplasticity in the context of addiction involves changes in synaptic connectivity, neuronal morphology, and molecular signaling pathways. Drug-evoked neuroplasticity in opioid addiction and withdrawal represents a complicated interaction between environmental, genetic, and epigenetic factors. Identifying specific transcriptional and epigenetic targets that can be modulated to restore normal neuroplasticity without disrupting essential physiological processes is a critical consideration. The discussion in this article focuses on the transcriptional aspects of drug-evoked neuroplasticity, emphasizing the role of key transcription factors, including cAMP response element-binding protein (CREB), ΔFosB, NF-kB, Myocyte-enhancing factor 2 (MEF2), Methyl-CpG binding protein 2 (MeCP2), E2F3a, and FOXO3a. These factors regulate gene expression and lead to the neuroadaptive changes observed in addiction and withdrawal. Epigenetic regulation, which involves modifying gene accessibility by controlling these structures, has been identified as a critical component of addiction development. By unraveling these complex molecular processes, this study provides valuable insights that may pave the way for future therapeutic interventions targeting the mechanisms underlying addiction and withdrawal.

Rett Syndrome: The Emerging Landscape of Treatment Strategies.

Rett syndrome (RTT) has enjoyed remarkable progress in achieving specific therapies. RTT, a unique neurodevelopmental disorder first described in 1966, progressed slowly until the landmark paper of Hagberg and colleagues in 1983. Thereafter, rapid advances were achieved including the development of specific diagnostic criteria and the active search for a genetic etiology, resulting 16 years later in identification of variants in the methyl-CpG-binding protein (MECP2) gene located at Xq28. Shortly thereafter, the NIH Office of Rare Diseases funded the RTT Natural History Study (NHS) in 2003, initiating the acquisition of natural history data on clinical features from a large population of individuals with RTT. This information was essential for advancement of clinical trials to provide specific therapies for this disorder. In the process, the International Rett Syndrome Association (IRSA) was formed (now the International Rett Syndrome Foundation-IRSF), which participated directly in encouraging and expanding enrollment in the NHS and, subsequently, in developing the SCOUT program to facilitate testing of potential therapeutic agents in a mouse model of RTT. The overall objective was to review clinical characteristics developed from the NHS and to discuss the status of specific therapies for this progressive neurodevelopmental disorder. The NHS study provided critical information on RTT: growth, anthropometrics, longevity, key comorbidities including epilepsy, breath abnormalities, gastroesophageal dysfunction, scoliosis and other orthopedic issues, puberty, behavior and anxiety, and progressive motor deterioration including the appearance of parkinsonian features. Phenotype-genotype correlations were noted including the role of X chromosome inactivation. Development of clinical severity and quality of life measures also proved critical for subsequent clinical trials. Further, development of biochemical and neurophysiologic biomarkers offered further endpoints for clinical trials. Initial clinical trials prior to the NHS were ineffective, but advances resulting from the NHS and other studies worldwide promoted significant interest from pharmaceutical firms resulting in several clinical trials. While some of these have been unrewarding such as sarizotan, others have been quite promising including the approval of trofinetide by the FDA in 2023 as the first agent available for specific treatment of RTT. Blarcamesine has been trialed in phase 3 trials, 14 agents have been studied in phase 2 trials, and 7 agents are being evaluated in preclinical/translational studies. A landmark study in 2007 by Guy et al. demonstrated that activation of a normal MECP2 gene in a null mouse model resulted in significant improvement. Gene replacement therapy has advanced through translational studies to two current phase 1/2 clinical trials (Taysha102 and Neurogene-401). Additional genetic therapies are also under study including gene editing, RNA editing, and X-chromosome reactivation. Taken together, progress in understanding and treating RTT over the past 40 years has been remarkable. This suggests that further advances can be expected.

MeCP2 Deficiency Alters the Response Selectivity of Prefrontal Cortical Neurons to Different Social Stimuli.

Rett syndrome (RTT), a severe neurodevelopmental disorder caused by mutations in the MeCP2 gene, is characterized by cognitive and social deficits. Previous studies have noted hypoactivity in the medial prefrontal cortex (mPFC) pyramidal neurons of MeCP2-deficient mice (RTT mice) in response to both social and nonsocial stimuli. To further understand the neural mechanisms behind the social deficits of RTT mice, we monitored excitatory pyramidal neurons in the prelimbic region of the mPFC during social interactions in mice. These neurons' activity was closely linked to social preference, especially in wild-type mice. However, RTT mice showed reduced social interest and corresponding hypoactivity in these neurons, indicating that impaired mPFC activity contributes to their social deficits. We identified six mPFC neural ensembles selectively tuned to various stimuli, with RTT mice recruiting fewer neurons to ensembles responsive to social interactions and consistently showing lower stimulus-ON ensemble transient rates. Despite these lower rates, RTT mice exhibited an increase in the percentage of social-ON neurons in later sessions, suggesting a compensatory mechanism for the decreased firing rate. This highlights the limited plasticity in the mPFC caused by MeCP2 deficiency and offers insights into the neural dynamics of social encoding. The presence of multifunctional neurons and those specifically responsive to social or object stimuli in the mPFC emphasizes its crucial role in complex behaviors and cognitive functions, with selective neuron engagement suggesting efficiency in neural activation that optimizes responses to environmental stimuli.