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Brain Stimulation 2023Rett syndrome (RTT), caused by mutations in the X-linked gene encoding methyl-CpG binding protein 2 (MeCP2), severely impairs learning and memory. We previously showed...
BACKGROUND
Rett syndrome (RTT), caused by mutations in the X-linked gene encoding methyl-CpG binding protein 2 (MeCP2), severely impairs learning and memory. We previously showed that forniceal deep brain stimulation (DBS) stimulates hippocampal neurogenesis with concomitant improvements in hippocampal-dependent learning and memory in a mouse model of RTT.
OBJECTIVES
To determine the duration of DBS benefits; characterize DBS effects on hippocampal neurogenesis; and determine whether DBS influences MECP2 genotype and survival of newborn dentate granular cells (DGCs) in RTT mice.
METHODS
Chronic DBS was delivered through an electrode implanted in the fimbria-fornix. We tested separate cohorts of mice in contextual and cued fear memory at different time points after DBS. We then examined neurogenesis, DGC apoptosis, and the expression of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) after DBS by immunohistochemistry.
RESULTS
After two weeks of forniceal DBS, memory improvements lasted between 6 and 9 weeks. Repeating DBS every 6 weeks was sufficient to maintain the improvement. Forniceal DBS stimulated the birth of more MeCP2-positive than MeCP2-negative DGCs and had no effect on DGC survival. It also increased the expression of BDNF but not VEGF in the RTT mouse dentate gyrus.
CONCLUSION
Improvements in learning and memory from forniceal DBS in RTT mice extends well beyond the treatment period and can be maintained by repeated DBS. Stimulation of BDNF expression correlates with improvements in hippocampal neurogenesis and memory benefits.
Topics: Mice; Animals; Rett Syndrome; Brain-Derived Neurotrophic Factor; Deep Brain Stimulation; Vascular Endothelial Growth Factor A; Hippocampus; Neurogenesis
PubMed: 37704033
DOI: 10.1016/j.brs.2023.09.002 -
Respiratory Physiology & Neurobiology Nov 2013Breathing disturbances are a major challenge in Rett Syndrome (RTT). These disturbances are more pronounced during wakefulness; but irregular breathing occurs also... (Review)
Review
Breathing disturbances are a major challenge in Rett Syndrome (RTT). These disturbances are more pronounced during wakefulness; but irregular breathing occurs also during sleep. During the day patients can exhibit alternating bouts of hypoventilation and irregular hyperventilation. But there is significant individual variability in severity, onset, duration and type of breathing disturbances. Research in mouse models of RTT suggests that different areas in the ventrolateral medulla and pons give rise to different aspects of this breathing disorder. Pre-clinical experiments in mouse models that target different neuromodulatory and neurotransmitter receptors and MeCP2 function within glia cells can partly reverse breathing abnormalities. The success in animal models raises optimism that one day it will be possible to control or potentially cure the devastating symptoms also in human patients with RTT.
Topics: Animals; Disease Models, Animal; Humans; Mice; Nerve Net; Respiration Disorders; Respiratory Mechanics; Rett Syndrome
PubMed: 23816600
DOI: 10.1016/j.resp.2013.06.022 -
Trends in Pharmacological Sciences Apr 2019Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the Methyl CpG binding protein 2 (MeCP2) gene. This Science & Society article focuses on... (Review)
Review
Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the Methyl CpG binding protein 2 (MeCP2) gene. This Science & Society article focuses on pharmacological strategies that attack RTT treatment from multiple angles, including drug repurposing and de novo discovery efforts, and discusses the impacts of preclinical study design and translationally relevant outcome measures.
Topics: Animals; Drug Discovery; Drug Evaluation, Preclinical; Drug Repositioning; Female; Humans; Methyl-CpG-Binding Protein 2; Mutation; Research Design; Rett Syndrome
PubMed: 30905360
DOI: 10.1016/j.tips.2019.02.007 -
Genes, Brain, and Behavior Jan 2022
Topics: Genetic Therapy; Humans; Methyl-CpG-Binding Protein 2; Phenotype; Rett Syndrome
PubMed: 34053173
DOI: 10.1111/gbb.12754 -
Neurobiology of Disease Aug 2016Rett syndrome is a devastating neurodevelopmental disorder, primarily caused by mutations of methyl CpG-binding protein 2 (MeCP2). Although the genetic cause of disease... (Review)
Review
Rett syndrome is a devastating neurodevelopmental disorder, primarily caused by mutations of methyl CpG-binding protein 2 (MeCP2). Although the genetic cause of disease was identified over a decade ago, a significant gap still remains in both our clinical and scientific understanding of its pathogenesis. Neurons are known to be primary players in pathology, with their dysfunction being the key in Rett syndrome. While studies in mice have demonstrated a clear causative - and potential therapeutic - role for neurons in Rett syndrome, recent work has suggested that other tissues also contribute significantly to progression of the disease. Indeed, Rett syndrome is known to present with several common peripheral pathologies, such as osteopenia, scoliosis, gastrointestinal problems including nutritional defects, and general growth deficit. Mouse models assessing the potential role of non-neuronal cell types have confirmed both roles in disease and potential therapeutic targets. A new picture is emerging in which neurons both initiate and drive pathology, while dysfunction of other cell types and peripheral tissues exacerbate disease, possibly amplifying further neurologic problems, and ultimately result in a positive feedback loop of progressively worsening symptoms. Here, we review what is known about neuronal and non-neuronal cell types, and discuss how this new, integrative understanding of the disease may allow for additional clinical and scientific pathways for treating and understanding Rett syndrome.
Topics: Animals; Humans; Rett Syndrome
PubMed: 25982834
DOI: 10.1016/j.nbd.2015.05.005 -
TheScientificWorldJournal Oct 2006Rett syndrome (RS) is a neuro-developmental syndrome of genetic origin, which mainly affects women. Individuals diagnosed with RS exhibit a variety of functional... (Review)
Review
Rett syndrome (RS) is a neuro-developmental syndrome of genetic origin, which mainly affects women. Individuals diagnosed with RS exhibit a variety of functional difficulties, which impair their quality of life. The variety of impairments and the differences between each child makes it necessary to administer skilled treatment, individually tailored to each client. Since the foundation of proper treatment is based on a structured, well administered, insightful assessment, the individual with RS with her complex array of difficulties should benefit from such a procedure. This notion has led to the establishment of the Israel Rett Syndrome Center. The center includes a medical branch located at the Safra Shildren's Medical Center at Tel Hashomer and an education/rehabilitation team, who performs assessments in special education facilities and residential settings throughout Israel. The assessment team works by means of arena assessment according to the concept of play-based assessment. This article presents the working model used by the education/rehabilitation team at the Israeli Rett Syndrome Center. The principles and working characteristics of the Israel Rett Syndrome Center team are suggested here as a potential model for establishing additional teams, presenting similar evaluation services for other individuals with RS as well as for analogous populations.
Topics: Female; Humans; Israel; Patient Care Team; Play Therapy; Program Evaluation; Rett Syndrome
PubMed: 17041719
DOI: 10.1100/tsw.2006.198 -
Neural Plasticity 2012Epigenetics refer to inheritable changes beyond DNA sequence that control cell identity and morphology. Epigenetics play key roles in development and cell fate... (Review)
Review
Epigenetics refer to inheritable changes beyond DNA sequence that control cell identity and morphology. Epigenetics play key roles in development and cell fate commitments and highly impact the etiology of many human diseases. A well-known link between epigenetics and human disease is the X-linked MECP2 gene, mutations in which lead to the neurological disorder, Rett Syndrome. Despite the fact that MeCP2 was discovered about 20 years ago, our current knowledge about its molecular function is not comprehensive. While MeCP2 was originally found to bind methylated DNA and interact with repressor complexes to inhibit and silence its genomic targets, recent studies have challenged this idea. Indeed, depending on its interacting protein partners and target genes, MeCP2 can act either as an activator or as a repressor. Furthermore, it is becoming evident that although Rett Syndrome is a progressive and postnatal neurological disorder, the consequences of MeCP2 deficiencies initiate much earlier and before birth. To comprehend the novel and challenging concepts in MeCP2 research and to design effective therapeutic strategies for Rett Syndrome, a targeted collaborative effort from scientists in multiple research areas to clinicians is required.
Topics: DNA Methylation; Epigenesis, Genetic; Humans; Methyl-CpG-Binding Protein 2; Mutation; Phenotype; Proteins; Rett Syndrome
PubMed: 22474603
DOI: 10.1155/2012/415825 -
Cells Feb 2019Rett syndrome (RTT) is a human neurodevelopmental disorder, whose pathogenesis has been linked to both oxidative stress and subclinical inflammatory status...
Rett syndrome (RTT) is a human neurodevelopmental disorder, whose pathogenesis has been linked to both oxidative stress and subclinical inflammatory status (OxInflammation). Methylglyoxal (MG), a glycolytic by-product with cytotoxic and pro-oxidant power, is the major precursor in vivo of advanced glycation end products (AGEs), which are known to exert their detrimental effect via receptor- (e.g., RAGE) or non-receptor-mediated mechanisms in several neurological diseases. On this basis, we aimed to compare fibroblasts from healthy subjects (CTR) with fibroblasts from RTT patients (N = 6 per group), by evaluating gene/protein expression patterns, and enzymatic activities of glyoxalases (GLOs), along with the levels of MG-dependent damage in both basal and MG-challenged conditions. Our results revealed that RTT is linked to an alteration of the GLOs system (specifically, increased GLO2 activity), that ensures unchanged MG-dependent damage levels. However, RTT cells underwent more pronounced cell death upon exogenous MG-treatment, as compared to CTR, and displayed lower RAGE levels than CTR, with no alterations following MG-treatment, thus suggesting that an adaptive response to dicarbonyl stress may occur. In conclusion, besides OxInflammation, RTT is associated with reshaping of the major defense systems against dicarbonyl stress, along with an altered cellular stress response towards pro-glycating insults.
Topics: Adolescent; Adult; Antigens, Neoplasm; Cell Survival; Child; Female; Fibroblasts; Glycosylation; Humans; Lactoylglutathione Lyase; Mitogen-Activated Protein Kinases; Pyruvaldehyde; Rett Syndrome; Thiolester Hydrolases; Young Adult
PubMed: 30781346
DOI: 10.3390/cells8020161 -
Developmental Medicine and Child... Apr 2013The aim of this study was to examine attention and recognition memory for faces and patterns in Rett syndrome, a severely disabling neurodevelopmental disorder caused by...
AIM
The aim of this study was to examine attention and recognition memory for faces and patterns in Rett syndrome, a severely disabling neurodevelopmental disorder caused by mutations in the X-linked MECP2 gene.
METHOD
Because Rett syndrome impairs speech and hand use, precluding most neuropsychological testing, the visual paired-comparison paradigm (VPC) was used, together with eye tracking. In the VPC, two identical stimuli are presented for familiarization. On test, the familiar stimulus and a new one are paired, and recognition inferred from preferential looking to the novel target. Attention is measured by looking time, gaze dispersion, and number/length of fixations. Twenty-seven female patients with Rett syndrome (mean age 10y 6mo; SD 6y 8mo, age range 2-22y) from the Rett clinic at a children's hospital were assessed in this study, along with 30 age- and sex-matched typically developing participants (outpatients from the same hospital).
RESULTS
Although patients with Rett syndrome showed recognition of both faces and patterns, with novelty scores greater than chance (50%), their performance was significantly poorer than that of the typically developing comparison group. Their attention to both was less mature and marked by a more narrowly focused gaze, with fewer and longer fixations. When inspecting faces, attention to the eyes was similar in both groups; however, patients with Rett syndrome tended to ignore the nose and mouth.
INTERPRETATION
This is one of the first studies to characterize attention and memory in individuals with Rett syndrome. Visually based techniques, such as the VPC, open a new avenue for quantifying the cognitive phenotype associated with this syndrome.
Topics: Adolescent; Attention; Case-Control Studies; Child; Child, Preschool; Eye Movements; Female; Humans; Methyl-CpG-Binding Protein 2; Mutation; Neuropsychological Tests; Recognition, Psychology; Rett Syndrome; Young Adult
PubMed: 23488948
DOI: 10.1111/dmcn.12085 -
Genes Dec 2023Inactivating mutations and the duplication of methyl-CpG binding protein 2 (MeCP2), respectively, mediate Rett syndrome (RTT) and duplication syndrome. These disorders...
Inactivating mutations and the duplication of methyl-CpG binding protein 2 (MeCP2), respectively, mediate Rett syndrome (RTT) and duplication syndrome. These disorders underscore the conceptual dose-dependent risk posed by gene therapy for mosaic RTT patients. Recently, a miRNA-Responsive Autoregulatory Element (miRARE) mitigated the dose-dependent toxicity posed by self-complementary adeno-associated viral vector serotype 9 (AAV9) mini gene therapy (scAAV9/mini) in mice. Here, we report an efficacy assessment for the human-ready version of this regulated gene therapy (TSHA-102) in male knockout (KO) mice after intracerebroventricular (ICV) administration at postnatal day 2 (P2) and after intrathecal (IT) administration at P7, P14 (±immunosuppression), and P28 (±immunosuppression). We also report qPCR studies on KO mice treated at P7-P35; protein analyses in KO mice treated at P38; and a survival safety study in female adult mice. In KO mice, TSHA-102 improved respiration, weight, and survival across multiple doses and treatment ages. TSHA-102 significantly improved the front average stance and swing times relative to the front average stride time after P14 administration of the highest dose for that treatment age. Viral genomic DNA and mini mRNA were present in the CNS. MiniMeCP2 protein expression was higher in the KO spinal cord compared to the brain. In female mice, TSHA-102 permitted survivals that were similar to those of vehicle-treated controls. In all, these pivotal data helped to support the regulatory approval to initiate a clinical trial for TSHA-102 in RTT patients (clinical trial identifier number NCT05606614).
Topics: Adult; Humans; Female; Male; Animals; Mice; Rett Syndrome; MicroRNAs; Mental Retardation, X-Linked; Brain; DNA, Viral; Genetic Therapy; Mice, Knockout
PubMed: 38254921
DOI: 10.3390/genes15010031