Pathophysiology Of RTT Research Articles

Rett syndrome.

Rett syndrome (RTT) is a severe, progressive, neurodevelopmental disorder, which affects predominantly females. In most cases, RTT is associated with pathogenic variants in MECP2. MeCP2, the protein product of MECP2, is known to regulate gene expression and is highly expressed in the brain. RTT is characterized by developmental regression of spoken language and hand use that, with hand stereotypies and impaired ambulation, constitute the four core diagnostic features. Affected individuals may present multiple other neurological impairments and comorbidities, such as seizures, breathing irregularities, anxiety and constipation. Studies employing neuroimaging, neuropathology, neurochemistry and animal models show reductions in brain size and global decreases in neuronal size, as well as alterations in multiple neurotransmitter systems. Management of RTT is mainly focused on preventing the progression of symptoms, currently improved by guidelines based on natural history studies. Animal and cellular models of MeCP2 deficiency have helped in understanding the pathophysiology of RTT and guided the development of trofinetide, an IGF1-related compound, which is an approved drug for RTT, as well as of other drugs and gene therapies currently under investigation.

Mitochondrial dysfunction and increased reactive oxygen species production in MECP2 mutant astrocytes and their impact on neurons

Studies on MECP2 function and its implications in Rett Syndrome (RTT) have traditionally centered on neurons. Here, using human embryonic stem cell (hESC) lines, we modeled MECP2 loss-of-function to explore its effects on astrocyte (AST) development and dysfunction in the brain. Ultrastructural analysis of RTT hESC-derived cerebral organoids revealed significantly smaller mitochondria compared to controls (CTRs), particularly pronounced in glia versus neurons. Employing a multiomics approach, we observed increased gene expression and accessibility of a subset of nuclear-encoded mitochondrial genes upon mutation of MECP2 in ASTs compared to neurons. Analysis of hESC-derived ASTs showed reduced mitochondrial respiration and altered key proteins in the tricarboxylic acid cycle and electron transport chain in RTT versus CTRs. Additionally, RTT ASTs exhibited increased cytosolic amino acids under basal conditions, which were depleted upon increased energy demands. Notably, mitochondria isolated from RTT ASTs exhibited increased reactive oxygen species and influenced neuronal activity when transferred to cortical neurons. These findings underscore MECP2 mutation's differential impact on mitochondrial and metabolic pathways in ASTs versus neurons, suggesting that dysfunctional AST mitochondria may contribute to RTT pathophysiology by affecting neuronal health.

Generation and Characterization of a Human Neuronal In Vitro Model for Rett Syndrome Using a Direct Reprogramming Method.

Rett Syndrome (RTT) is a severe neurodevelopmental disorder, afflicting 1 in 10,000 female births. It is caused by mutations in the X-linked methyl-CpG-binding protein gene (MECP2), which encodes for the global transcriptional regulator methyl CpG binding protein 2 (MeCP2). As human brain samples of RTT patients are scarce and cannot be used for downstream studies, there is a pressing need for in vitro modeling of pathological neuronal changes. In this study, we use a direct reprogramming method for the generation of neuronal cells from MeCP2-deficient and wild-type human dermal fibroblasts using two episomal plasmids encoding the transcription factors SOX2 and PAX6. We demonstrated that the obtained neurons exhibit a typical neuronal morphology and express the appropriate marker proteins. RNA-sequencing confirmed neuronal identity of the obtained MeCP2-deficient and wild-type neurons. Furthermore, these MeCP2-deficient neurons reflect the pathophysiology of RTT in vitro, with diminished dendritic arborization and hyperacetylation of histone H3 and H4. Treatment with MeCP2, tethered to the cell penetrating peptide TAT, ameliorated hyperacetylation of H4K16 in MeCP2-deficient neurons, which strengthens the RTT relevance of this cell model. We generated a neuronal model based on direct reprogramming derived from patient fibroblasts, providing a powerful tool to study disease mechanisms and investigating novel treatment options for RTT.

A281 CASE REPORT: STEATOTIC LIVER DISEASE DIAGNOSED IN A 24-YEAR-OLD FEMALE WITH RETT SYNDROME

Abstract Background Rett syndrome (RTT) is a rare, severe neurodevelopmental disorder seen almost exclusively in females that is caused by spontaneous loss-of-function mutations in the methyl CpG binding protein 2 (MECP2) gene. Girls with RTT typically demonstrate normal development for the first 6-18 months of life before displaying evidence of variable levels of developmental milestone regression and physical disability. Although perturbed lipid metabolism in the nervous system is the main contributor to the pathophysiology of RTT, mutations to the MECP2 gene also contribute to disease burden by causing perturbations to peripheral systems, leading to consequences such as dyslipidemia (DLD) and steatotic liver disease (SLD). Although DLD has been described in human cell lines and girls with RTT, SLD has only been described in RTT mouse models. Aims This report aims to present a case of a patient with RTT who was diagnosed with SLD on liver biopsy in the context of DLD but without insulin resistance or other comorbidities associated with metabolic syndrome. Methods Retrospective review of one patient. Results A 24-year-old woman with genetically proven RTT (T158M point mutation to MECP2) complicated by several physical disabilities was seen at a tertiary care center clinic for evaluation of abnormal liver enzymes (ALT 163, AST 51, ALP 258, total bilirubin 6). Abdominal ultrasound demonstrated moderately echogenic liver parenchyma consistent with hepatic steatosis. Additional investigations for an etiology were unremarkable and the patient had no history of alcohol misuse or the use of new medications or supplements. Regarding risk factors for SLD, her homeostatic model assessment for insulin resistance (HOMA-IR) score was 1.8, hemoglobin A1c was 4.8%, and her lipid profile demonstrated elevated triglycerides and LDL, in keeping with DLD. The decision was made to proceed with a liver biopsy. This demonstrated moderate steatosis and no ballooning, categorized as grade A1 and stage F1. Conclusions This case demonstrates that RTT patients have similar lipid metabolism perturbations to those seen in MECP2-null mouse models, resulting in similar metabolic abnormalities such as DLD and SLD. The absence of insulin resistance and other comorbidities associated with metabolic syndrome further support these perturbations are caused by a pathophysiologic mechanism specific to RTT. This demonstrates the importance of screening RTT patients for DLD and SLD despite their young age to detect these conditions before complications arise. It also demonstrates that MECP2-null mice can be used as reliable models to identify future therapies for RTT, such as ketogenic diet, ω-3 PUFAs supplementation, and lipid-lowering statin therapy. Funding Agencies None

Zebrafish in understanding molecular pathophysiology, disease modeling, and developing effective treatments for Rett syndrome.

Rett syndrome (RTT) is a rare but dreadful X-linked genetic disease that mainly affects young girls. It is a neurological disease that affects nerve cell development and function, resulting in severe motor and intellectual disabilities. To date, no cure is available for treating this disease. In 90% of the cases, RTT is caused by a mutation in methyl-CpG-binding protein 2 (MECP2), a transcription factor involved in the repression and activation of transcription. MECP2 is known to regulate several target genes and is involved in different physiological functions. Mouse models exhibit a broad range of phenotypes in recapitulating human RTT symptoms; however, understanding the disease mechanisms remains incomplete, and many potential RTT treatments developed in mouse models have not shown translational effectiveness in human trials. Recent data hint that the zebrafish model emulates similar disrupted neurological functions following mutation of the mecp2 gene. This suggests that zebrafish can be used to understand the onset and progression of RTT pathophysiology and develop a possible cure. In this review, we elaborate on the molecular basis of RTT pathophysiology in humans and model organisms, including rodents and zebrafish, focusing on the zebrafish model to understand the molecular pathophysiology and the development of therapeutic strategies for RTT. Finally, we propose a rational treatment strategy, including antisense oligonucleotides, small interfering RNA technology and induced pluripotent stem cell-derived cell therapy.

A circuit-level biomarker of Rett syndrome based on ectopic phase-amplitude coupling during slow-wave-sleep.

Rett syndrome (RTT) is a neurodevelopmental disorder characterized by loss of purposeful hand use and spoken language following an initial period of normal development. Although much is known about the genetic and molecular underpinnings of RTT, less is known about the circuit-level etiopathology. Coupling of oscillations during slow-wave-sleep (SWS) underlies important neurocognitive processes in adulthood, yet its emergence has yet to be described in early typical development (TD) or in RTT. We therefore addressed these unknowns by describing SWS cross-frequency coupling in both RTT and early TD using a retrospective study design. We found that in TD, phase-amplitude coupling (PAC) during SWS was dominated by coupling of slow-wave (0.5-2Hz) phase to theta amplitude (5-8Hz, "SW:T") as well as slow-wave to spindle-range (12-15Hz, "SW:S"). Coupling exhibited characteristic vertex-prominent spatial topography, which emerged during an early developmental window. This topography failed to develop in patients with RTT due to persistent ectopic coupling. Furthermore, we found that subtypes of RTT exhibit distinct PAC topographic profiles, and that ectopic PAC correlates with clinical severity. These findings suggest that altered PAC dynamics and spatial organization during SWS may underlie the circuit-level pathophysiology of RTT and suggest that ectopic coupling may contribute to RTT pathogenesis.

Comprehensive Volumetric Analysis of Mecp2-Null Mouse Model for Rett Syndrome by T2-Weighted 3D Magnetic Resonance Imaging.

Rett syndrome (RTT) is a severe progressive neurodevelopmental disorder characterized by various neurological symptoms. Almost all RTT cases are caused by mutations in the X-linked methyl-CpG-binding protein 2 (MeCP2) gene, and several mouse models have been established to understand the disease. However, the neuroanatomical abnormalities in each brain region of RTT mouse models have not been fully understood. Here, we investigated the global and local neuroanatomy of the Mecp2 gene-deleted RTT model (Mecp2-KO) mouse brain using T2-weighted 3D magnetic resonance imaging with different morphometry to clarify the brain structural abnormalities that are involved in the pathophysiology of RTT. We found a significant reduction in global and almost all local volumes in the brain of Mecp2-KO mice. In addition, a detailed comparative analysis identified specific volume reductions in several brain regions in the Mecp2-deficient brain. Our analysis also revealed that the Mecp2-deficient brain shows changes in hemispheric asymmetry in several brain regions. These findings suggest that MeCP2 affects not only the whole-brain volume but also the region-specific brain structure. Our study provides a framework for neuroanatomical studies of a mouse model of 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.

Region-Specific KCC2 Rescue by rhIGF-1 and Oxytocin in a Mouse Model of Rett Syndrome.

Rett syndrome (RTT) is characterized by dysfunction in neuronal excitation/inhibition (E/I) balance, potentially impacting seizure susceptibility via deficits in K+/Cl- cotransporter 2 (KCC2) function. Mice lacking the Methyl-CpG binding protein 2 (MeCP2) recapitulate many symptoms of RTT, and recombinant human insulin-like growth factor-1 (rhIGF-1) restores KCC2 expression and E/I balance in MeCP2 KO mice. However, clinical trial outcomes of rhIGF-1 in RTT have been variable, and increasing its therapeutic efficacy is highly desirable. To this end, the neuropeptide oxytocin (OXT) is promising, as it also critically modulates KCC2 function during early postnatal development. We measured basal KCC2 expression levels in MeCP2 KO mice and identified 3 key frontal brain regions showing KCC2 alterations in young adult mice, but not in postnatal P10 animals. We hypothesized that deficits in an IGF-1/OXT signaling crosstalk modulating KCC2 may occur in RTT during postnatal development. Consistently, we detected alterations of IGF-1 receptor and OXT receptor levels in those brain areas. rhIGF-1 and OXT treatments in KO mice rescued KCC2 expression in a region-specific and complementary manner. These results suggest that region-selective combinatorial pharmacotherapeutic strategies could be most effective at normalizing E/I balance in key brain regions subtending the RTT pathophysiology.

Reviewing Evidence for the Relationship of EEG Abnormalities and RTT Phenotype Paralleled by Insights from Animal Studies.

Rett syndrome (RTT) is a rare neurodevelopmental disorder that is usually caused by mutations of the MECP2 gene. Patients with RTT suffer from severe deficits in motor, perceptual and cognitive domains. Electroencephalogram (EEG) has provided useful information to clinicians and scientists, from the very first descriptions of RTT, and yet no reliable neurophysiological biomarkers related to the pathophysiology of the disorder or symptom severity have been identified to date. To identify consistently observed and potentially informative EEG characteristics of RTT pathophysiology, and ascertain areas most worthy of further systematic investigation, here we review the literature for EEG abnormalities reported in patients with RTT and in its disease models. While pointing to some promising potential EEG biomarkers of RTT, our review identify areas of need to realize the potential of EEG including (1) quantitative investigation of promising clinical-EEG observations in RTT, e.g., shift of mu rhythm frequency and EEG during sleep; (2) closer alignment of approaches between patients with RTT and its animal models to strengthen the translational significance of the work (e.g., EEG measurements and behavioral states); (3) establishment of large-scale consortium research, to provide adequate Ns to investigate age and genotype effects.

Proteomic profiling reveals mitochondrial alterations in Rett syndrome

Rett syndrome (RTT) is a pervasive neurodevelopmental disorder associated with mutation in MECP2 gene. Despite a well-defined genetic cause, there is a growing consensus that a metabolic component could play a pivotal role in RTT pathophysiology. Indeed, perturbed redox homeostasis and inflammation, i.e. oxinflammation, with mitochondria dysfunction as the central hub between the two phenomena, appear as possible key contributing factors to RTT pathogenesis and its clinical features. While these RTT-related changes have been widely documented by transcriptomic profiling, proteomics studies supporting these evidences are still limited.Here, using primary dermal fibroblasts from control and patients, we perform a large-scale proteomic analysis that, together with data mining approaches, allow us to carry out the first comprehensive characterization of RTT cellular proteome, showing mainly changes in expression of proteins involved in the mitochondrial network. These findings parallel with an altered expression of key mediators of mitochondrial dynamics and mitophagy associated with abnormal mitochondrial morphology. In conclusion, our proteomic analysis confirms the pathological relevance of mitochondrial dysfunction in RTT pathogenesis and progression.

Sensory evoked potentials in patients with Rett syndrome through the lens of animal studies: Systematic review

ObjectiveSystematically review the abnormalities in event related potential (ERP) recorded in Rett Syndrome (RTT) patients and animals in search of translational biomarkers of deficits related to the particular neurophysiological processes of known genetic origin (MECP2 mutations). MethodsPubmed, ISI Web of Knowledge and BIORXIV were searched for the relevant articles according to PRISMA standards. ResultsERP components are generally delayed across all sensory modalities both in RTT patients and its animal model, while findings on ERPs amplitude strongly depend on stimulus properties and presentation rate. Studies on RTT animal models uncovered the abnormalities in the excitatory and inhibitory transmission as critical mechanisms underlying the ERPs changes, but showed that even similar ERP alterations in auditory and visual domains have a diverse neural basis. A range of novel approaches has been developed in animal studies bringing along the meaningful neurophysiological interpretation of ERP measures in RTT patients. ConclusionsWhile there is a clear evidence for sensory ERPs abnormalities in RTT, to further advance the field there is a need in a large-scale ERP studies with the functionally-relevant experimental paradigms. SignificanceThe review provides insights into domain-specific neural basis of the ERP abnormalities and promotes clinical application of the ERP measures as the non-invasive functional biomarkers of RTT pathophysiology.

Proteomic analyses reveal misregulation of LIN28 expression and delayed timing of glial differentiation in human iPS cells with MECP2 loss-of-function.

Rett syndrome (RTT) is a pervasive developmental disorder caused by mutations in MECP2. Complete loss of MECP2 function in males causes congenital encephalopathy, neurodevelopmental arrest, and early lethality. Induced pluripotent stem cell (iPSC) lines from male patients harboring mutations in MECP2, along with control lines from their unaffected fathers, give us an opportunity to identify some of the earliest cellular and molecular changes associated with MECP2 loss-of-function (LOF). We differentiated iPSC-derived neural progenitor cells (NPCs) using retinoic acid (RA) and found that astrocyte differentiation is perturbed in iPSC lines derived from two different patients. Using highly stringent quantitative proteomic analyses, we found that LIN28, a gene important for cell fate regulation and developmental timing, is upregulated in mutant NPCs compared to WT controls. Overexpression of LIN28 protein in control NPCs suppressed astrocyte differentiation and reduced neuronal synapse density, whereas downregulation of LIN28 expression in mutant NPCs partially rescued this synaptic deficiency. These results indicate that the pathophysiology of RTT may be caused in part by misregulation of developmental timing in neural progenitors, and the subsequent consequences of this disruption on neuronal and glial differentiation.

Reestablishment of adenosine levels: a possible strategy for Rett Syndrome

Reestablishment of adenosine levels: a possible strategy for Rett Syndrome

Activation of the Medial Prefrontal Cortex Reverses Cognitive and Respiratory Symptoms in a Mouse Model of Rett Syndrome.

Rett syndrome (RTT) is a severe neurodevelopmental disorder caused by loss-of-function mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2; Amir et al., 1999), a transcriptional regulatory protein (Klose et al., 2005). Mouse models of RTT (Mecp2 mutants) exhibit excitatory hypoconnectivity in the medial prefrontal cortex (mPFC; Sceniak et al., 2015), a region critical for functions that are abnormal in RTT patients, ranging from learning and memory to regulation of visceral homeostasis (Riga et al., 2014). The present study was designed to test the hypothesis that increasing the activity of mPFC pyramidal neurons in heterozygous female Mecp2 mutants (Hets) would ameliorate RTT-like symptoms, including deficits in respiratory control and long-term retrieval of auditory conditioned fear. Selective activation of mPFC pyramidal neurons in adult animals was achieved by bilateral infection with an AAV8 vector expressing excitatory hm3D(Gq) DREADD (Designer Receptors Exclusively Activated by Designer Drugs) (Armbruster et al., 2007) under the control of the CamKIIa promoter. DREADD activation in Mecp2 Hets completely restored long-term retrieval of auditory conditioned fear, eliminated respiratory apneas, and reduced respiratory frequency variability to wild-type (Wt) levels. Reversal of respiratory symptoms following mPFC activation was associated with normalization of Fos protein levels, a marker of neuronal activity, in a subset of brainstem respiratory neurons. Thus, despite reduced levels of MeCP2 and severe neurological deficits, mPFC circuits in Het mice are sufficiently intact to generate normal behavioral output when pyramidal cell activity is increased. These findings highlight the contribution of mPFC hypofunction to the pathophysiology of RTT and raise the possibility that selective activation of cortical regions such as the mPFC could provide therapeutic benefit to RTT patients.

RNA sequencing and proteomics approaches reveal novel deficits in the cortex of Mecp2-deficient mice, a model for Rett syndrome

BackgroundRett syndrome (RTT) is an X-linked neurodevelopmental disorder caused by mutations in the transcriptional regulator MeCP2. Much of our understanding of MeCP2 function is derived from transcriptomic studies with the general assumption that alterations in the transcriptome correlate with proteomic changes. Advances in mass spectrometry-based proteomics have facilitated recent interest in the examination of global protein expression to better understand the biology between transcriptional and translational regulation.MethodsWe therefore performed the first comprehensive transcriptome-proteome comparison in a RTT mouse model to elucidate RTT pathophysiology, identify potential therapeutic targets, and further our understanding of MeCP2 function. The whole cortex of wild-type and symptomatic RTT male littermates (n = 4 per genotype) were analyzed using RNA-sequencing and data-independent acquisition liquid chromatography tandem mass spectrometry. Ingenuity® Pathway Analysis was used to identify significantly affected pathways in the transcriptomic and proteomic data sets.ResultsOur results indicate these two “omics” data sets supplement one another. In addition to confirming previous works regarding mRNA expression in Mecp2-deficient animals, the current study identified hundreds of novel protein targets. Several selected protein targets were validated by Western blot analysis. These data indicate RNA metabolism, proteostasis, monoamine metabolism, and cholesterol synthesis are disrupted in the RTT proteome. Hits common to both data sets indicate disrupted cellular metabolism, calcium signaling, protein stability, DNA binding, and cytoskeletal cell structure. Finally, in addition to confirming disrupted pathways and identifying novel hits in neuronal structure and synaptic transmission, our data indicate aberrant myelination, inflammation, and vascular disruption. Intriguingly, there is no evidence of reactive gliosis, but instead, gene, protein, and pathway analysis suggest astrocytic maturation and morphological deficits.ConclusionsThis comparative omics analysis supports previous works indicating widespread CNS dysfunction and may serve as a valuable resource for those interested in cellular dysfunction in RTT.

The BDNF val-66-met Polymorphism Affects Neuronal Morphology and Synaptic Transmission in Cultured Hippocampal Neurons from Rett Syndrome Mice.

Brain-derived neurotrophic factor (Bdnf) has been implicated in several neurological disorders including Rett syndrome (RTT), an X-linked neurodevelopmental disorder caused by loss-of-function mutations in the transcriptional modulator methyl-CpG-binding protein 2 (MECP2). The human BDNF gene has a single nucleotide polymorphism (SNP)—a methionine (met) substitution for valine (val) at codon 66—that affects BDNF’s trafficking and activity-dependent release and results in cognitive dysfunction. Humans that are carriers of the met-BDNF allele have subclinical memory deficits and reduced hippocampal volume and activation. It is still unclear whether this BDNF SNP affects the clinical outcome of RTT individuals. To evaluate whether this BDNF SNP contributes to RTT pathophysiology, we examined the consequences of expression of either val-BDNF or met-BDNF on dendrite and dendritic spine morphology, and synaptic function in cultured hippocampal neurons from wildtype (WT) and Mecp2 knockout (KO) mice. Our findings revealed that met-BDNF does not increase dendritic growth and branching, dendritic spine density and individual spine volume, and the number of excitatory synapses in WT neurons, as val-BDNF does. Furthermore, met-BDNF reduces dendritic complexity, dendritic spine volume and quantal excitatory synaptic transmission in Mecp2 KO neurons. These results suggest that the val-BDNF variant contributes to RTT pathophysiology, and that BDNF-based therapies should take into consideration the BDNF genotype of the RTT individuals.

Negative Allosteric Modulation of mGluR5 Partially Corrects Pathophysiology in a Mouse Model of Rett Syndrome.

Altered regulation of synaptic protein synthesis has been hypothesized to contribute to the pathophysiology that underlies multiple forms of intellectual disability and autism spectrum disorder. Here, we show in a mouse model of Rett syndrome (Mecp2 KO) that metabotropic glutamate receptor 5 (mGluR5)- and protein-synthesis-dependent synaptic plasticity are abnormal in the hippocampus. We found that a subset of ribosome-bound mRNAs was aberrantly upregulated in hippocampal CA1 neurons of Mecp2 KO mice, that these significantly overlapped with FMRP direct targets and/or SFARI human autism genes, and that chronic treatment of Mecp2 KO mice with an mGluR5-negative allosteric modulator tunes down upregulated ribosome-bound mRNAs and partially improves mutant mice phenotypes.

Therapeutic Potential of Transcranial Focused Ultrasound for Rett Syndrome.

Rett syndrome (RTT) is a severe neurodevelopmental disorder occurring almost exclusively in females and is caused by loss-of-function mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2) in the majority of cases. MeCP2 is essential for the normal function of nerve cells, including neuronal development, maturation, and synaptic activity. RTT is characterized by normal early development followed by autistic-like features, slowed brain and head growth, gait abnormalities, seizures, breathing irregularities, and cognitive disabilities. Medical management in RTT remains supportive and symptomatic. Brain-derived neurotrophic factor (BDNF) has been implicated in the pathophysiology of RTT. Recent studies have shown a phenotypic reversal by increasing BDNF expression in a RTT mouse model. Thus, manipulation of BDNF expression/signaling in the brain could be therapeutic for this disease. Transcranial focused ultrasound for (tFUS) can noninvasively focally modulate human cortical function, stimulate neurogenesis, and increase BDNF in animal studies. Consequently, tFUS may be of therapeutic potential for Rett syndrome. Further evaluation of the therapeutic effects of tFUS in Mecp2 deficient animal models is needed before clinical trials can begin.

Loss of MeCP2 disrupts cell autonomous and autocrine BDNF signaling in mouse glutamatergic neurons.

Mutations in the MECP2 gene cause the neurodevelopmental disorder Rett syndrome (RTT). Previous studies have shown that altered MeCP2 levels result in aberrant neurite outgrowth and glutamatergic synapse formation. However, causal molecular mechanisms are not well understood since MeCP2 is known to regulate transcription of a wide range of target genes. Here, we describe a key role for a constitutive BDNF feed forward signaling pathway in regulating synaptic response, general growth and differentiation of glutamatergic neurons. Chronic block of TrkB receptors mimics the MeCP2 deficiency in wildtype glutamatergic neurons, while re-expression of BDNF quantitatively rescues MeCP2 deficiency. We show that BDNF acts cell autonomous and autocrine, as wildtype neurons are not capable of rescuing growth deficits in neighboring MeCP2 deficient neurons in vitro and in vivo. These findings are relevant for understanding RTT pathophysiology, wherein wildtype and mutant neurons are intermixed throughout the nervous system.