Mecp2 KO Mice Research Articles

5-HT1A Receptor Agonist Treatment Partially Ameliorates Rett Syndrome Phenotypes in mecp2-Null Mice by Rescuing Impairment of Neuron Transmission and the CREB/BDNF Signaling Pathway.

Rett syndrome (RTT) is an X-linked neurodevelopmental disorder caused by mutations in the gene that encodes methyl CpG-binding protein 2 (MECP2) and is characterized by the loss of acquired motor and language skills, stereotypic movements, respiratory abnormalities and autistic features. There has been no effective treatment for this disorder until now. In this study, we used a Mecp2-null (KO) mouse model of RTT to investigate whether repeated intraperitoneal treatment with the 5-HT1A receptor agonist tandospirone could improve the RTT phenotype. The results showed that administration of tandospirone significantly extended the lifespan of Mecp2-KO mice and obviously ameliorated RTT phenotypes, including general condition, hindlimb clasping, gait, tremor and breathing in Mecp2-KO mice. Tandospirone treatment significantly improved the impairment in GABAergic, glutaminergic, dopaminergic and serotoninergic neurotransmission in the brainstem of Mecp2-KO mice. Decreased dopaminergic neurotransmission in the cerebellum of Mecp2-KO mice was also significantly increased by tandospirone treatment. Moreover, RNA-sequencing analysis found that tandospirone modulates the RTT phenotype, partially through the CREB1/BDNF signaling pathway in Mecp2-KO mice. These findings provide a new option for clinical treatment.

MeCP2 loss-of-function dysregulates microRNAs regionally and disrupts excitatory/inhibitory synaptic transmission balance.

Rett syndrome is a leading cause of intellectual disability in females primarily caused by loss of function mutations in the transcriptional regulator MeCP2. Loss of MeCP2 leads to a host of synaptic phenotypes that are believed to underlie Rett syndrome pathophysiology. Synaptic deficits vary by brain region upon MeCP2 loss, suggesting distinct molecular alterations leading to disparate synaptic outcomes. In this study, we examined the contribution of MeCP2's newly described role in miRNA regulation to regional molecular and synaptic impairments. Two miRNAs, miR-101a and miR-203, were identified and confirmed as upregulated in MeCP2 KO mice in the hippocampus and cortex, respectively. miR-101a overexpression in hippocampal cultures led to opposing effects at excitatory and inhibitory synapses and in spontaneous and evoked neurotransmission, revealing the potential for a single miRNA to broadly regulate synapse function in the hippocampus. These results highlight the importance of regional alterations in miRNA expression and the specific impact on synaptic function with potential implications for Rett syndrome.

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.

Vitamin D Supplementation Partially Rescues Breathing Deficits in Mecp2 Hemizygous Null Mice, a Model of Rett Syndrome

Rett syndrome (RTT) is a severe X‐linked progressive neurodevelopmental disorder affecting ~1 in 10,000 females. It is the second most common genetic cause of cognitive disability in girls, after Down syndrome. Girls with this devastating disorder develop relatively normally for 6‐18 months, after which they undergo a period of rapid regression. They lose many motor skills, the growth of their brain slows, and they develop repetitive, autistic behaviors and seizures. Autonomic disruptions are a leading cause of early death in RTT, and rescue of breathing deficits is considered a primary goal in the development of therapeutic interventions. We initiated a proof‐of‐concept study by investigating male Mecp2 hemizygous null mice as they have the strongest phenotype which occurs at an early age; male Mecp2‐null (KO) mice have also been characterized thoroughly in the literature. We tested the hypothesis that Vitamin D supplementation (VitD) would ameliorate, or partially rescue breathing and cardiovascular deficits in Mecp2 KO mice. Mice were tested at 4 weeks of age (PRE), then placed on a control (1 IU Vitamin D/g) or VitD (50 IU Vitamin D/g) diet, and re‐tested at 8 weeks of age (POST). To examine our hypothesis, unrestrained barometric plethysmography was used to quantify breathing frequency (breaths/min), tidal volume (VT; mL/breath), VT/inspiratory time (VT/Ti; mL/sec), minute ventilation (VE; mL/min/g) and the ventilatory equivalent for CO2 (VE/VCO2) in both wildtype (WT; n=6) and Mecp2 KO (n=5) littermates. Data Sciences International Ponemah software was used to analyze flow tracings during exposure to air (20.93% O2, balanced N2). The MouseOx Plus by STARR Life Sciences was utilized to collect heart rate (HR) and oxygen saturation in freely moving conscious mice. Data are expressed as mean ± S.D., WT vs. KO. In the PRE group, Mecp2 KO mice had dysregulated breathing and HR as previously demonstrated in the literature (data not shown). In the POST VitD diet groups, VT (0.24±0.02 vs 0.15±0.06 mL/breath; p=0.01) and VT/Ti remained lower (2.085±0.313 vs. 1.291±0.583 mL/sec; p=0.017) in Mecp2 KO. However, breathing frequency (166±21 vs. 166±19 breaths/min), VE/g (1.07±0.12 vs. 0.99±0.57 mL/min/g), ratio of VE/VCO2 (112±47 vs. 103±46) and HR (582±84 vs. 532±59 beats/min) were similar between WT and KO. The number of oxygen desaturations were not significant between WT and KO, but the values were variable across groups and included a number of desaturations (12±7 vs. 5±7 desaturations/30 minutes), similar to findings we have previously described in young control mice. These data reveal a partial rescue of breathing and HR deficits in Mecp2 KO mice following 4 weeks of VitD. The reduced VT/Ti suggests an attenuated neural drive to breath in Mecp2 KO vs. WT that persists after VitD. Current studies are examining the responses to hypoxia and hypercapnia and will identify more information about oxygen and carbon dioxide sensing in these mice following control and VitD diets.

Analysis of Astroglial Secretomic Profile in the Mecp2-Deficient Male Mouse Model of Rett Syndrome.

Mutations in the X-linked MECP2 gene are responsible for Rett syndrome (RTT), a severe neurological disorder. MECP2 is a transcriptional modulator that finely regulates the expression of many genes, specifically in the central nervous system. Several studies have functionally linked the loss of MECP2 in astrocytes to the appearance and progression of the RTT phenotype in a non-cell autonomous manner and mechanisms are still unknown. Here, we used primary astroglial cells from Mecp2-deficient (KO) pups to identify deregulated secreted proteins. Using a differential quantitative proteomic analysis, twenty-nine proteins have been identified and four were confirmed by Western blotting with new samples as significantly deregulated. To further verify the functional relevance of these proteins in RTT, we tested their effects on the dendritic morphology of primary cortical neurons from Mecp2 KO mice that are known to display shorter dendritic processes. Using Sholl analysis, we found that incubation with Lcn2 or Lgals3 for 48 h was able to significantly increase the dendritic arborization of Mecp2 KO neurons. To our knowledge, this study, through secretomic analysis, is the first to identify astroglial secreted proteins involved in the neuronal RTT phenotype in vitro, which could open new therapeutic avenues for the treatment of Rett syndrome.

An Astrocytic Influence on Impaired Tonic Inhibition in Hippocampal CA1 Pyramidal Neurons in a Mouse Model of Rett Syndrome.

Rett syndrome (RTT) is a severe neurodevelopmental disease caused by mutations in the methyl-CpG binding protein 2 (MECP2) gene. Although altered interneuron development and function are clearly demonstrated in RTT mice, a particular mode of inhibition, tonic inhibition, has not been carefully examined. We report here that tonic inhibition is significantly reduced in pyramidal neurons in the CA1 region of the hippocampus in mice where Mecp2 is deleted either in all cells or specifically in astrocytes. Since no change is detected in the level of GABA receptors, such a reduction in tonic inhibition is likely a result of decreased ambient GABA level in the extracellular space. Consistent with this explanation, we observed increased expression of a GABA transporter, GABA transporter 3 (GAT3), in the hippocampus of the Mecp2 KO mice, as well as a corresponding increase of GAT3 current in hippocampal astrocytes. These phenotypes are relevant to RTT because pharmacological blockage of GAT3 can normalize tonic inhibition and intrinsic excitability in CA1 pyramidal neurons, and rescue the phenotype of increased network excitability in acute hippocampal slices from the Mecp2 KO mice. Finally, chronic administration of a GAT3 antagonist improved a composite symptom score and extended lifespan in the Mecp2 KO mice. Only male mice were used in this study. These results not only advance our understanding of RTT etiology by defining a new neuronal phenotype and revealing how it can be influenced by astrocytic alterations, but also reveal potential targets for intervention.SIGNIFICANCE STATEMENT Our study reports a novel phenotype of reduced tonic inhibition in hippocampal CA1 pyramidal neurons in the Rett syndrome mice, reveal a potential mechanism of increased GABA transporter expression/activity in the neighboring astrocytes, describe a disease-relevant consequence in hyperexcitability, and provide preliminary evidence that targeting this phenotype may slow down disease progression in Rett syndrome mice. These results help our understanding of the disease etiology and identify a new therapeutic target for treating Rett syndrome.

Dendrimer-conjugated glutaminase inhibitor selectively targets microglial glutaminase in a mouse model of Rett syndrome.

Background: Elevated glutamate production and release from glial cells is a common feature of many CNS disorders. Inhibitors of glutaminase (GLS), the enzyme responsible for converting glutamine to glutamate have been developed to target glutamate overproduction. However, many GLS inhibitors have poor aqueous solubility, are unable to cross the blood brain barrier, or demonstrate significant toxicity when given systemically, precluding translation. Enhanced aqueous solubility and systemic therapy targeted to activated glia may address this challenge. Here we examine the impact of microglial-targeted GLS inhibition in a mouse model of Rett syndrome (RTT), a developmental disorder with no viable therapies, manifesting profound central nervous system effects, in which elevated glutamatergic tone, upregulation of microglial GLS, oxidative stress and neuroimmune dysregulation are key features.Methods: To enable this, we conjugated a potent glutaminase inhibitor, N-(5-{2-[2-(5-amino-[1,3,4]thiadiazol-2-yl)-ethylsulfanyl]-ethyl}-[1,3,4]thiadiazol-2-yl)-2-phenyl-acetamide (JHU29) to a generation 4 hydroxyl PAMAM dendrimer (D-JHU29). We then examined the effect of D-JHU29 in organotypic slice culture on glutamate release. We also examined GLS activity in microglial and non-microglial cells, and neurobehavioral phenotype after systemic administration of D-JHU29 in a mouse model of RTT.Results: We report successful conjugation of JHU29 to dendrimer resulting in enhanced water solubility compared to free JHU29. D-JHU29 reduced the excessive glutamate release observed in tissue culture slices in a clinically relevant Mecp2-knockout (KO) RTT mouse. Microglia isolated from Mecp2-KO mice demonstrated upregulation of GLS activity that normalized to wild-type levels following systemic treatment with D-JHU29. Neurobehavioral assessments in D-JHU29 treated Mecp2-KO mice revealed selective improvements in mobility.Conclusion: These findings demonstrate that glutaminase inhibitors conjugated to dendrimers are a viable mechanism to selectively inhibit microglial GLS to reduce glutamate production and improve mobility in a mouse model of RTT, with broader implications for selectively targeting this pathway in other neurodegenerative disorders.

Correcting deregulated Fxyd1 expression rescues deficits in neuronal arborization and potassium homeostasis in MeCP2 deficient male mice

Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the MECP2 gene. In the absence of MeCP2, expression of FXYD domain-containing transport regulator 1 (FXYD1) is deregulated in the frontal cortex (FC) of mice and humans. Because Fxyd1 is a membrane protein that controls cell excitability by modulating Na+, K+-ATPase activity (NKA), an excess of Fxyd1 may reduce NKA activity and contribute to the neuronal phenotype of Mecp2 deficient (KO) mice. To determine if Fxyd1 can rescue these RTT deficits, we studied the male progeny of Fxyd1 null males bred to heterozygous Mecp2 female mice. Maximal NKA enzymatic activity was not altered by the loss of MeCP2, but it increased in mice lacking one Fxyd1 allele, suggesting that NKA activity is under Fxyd1 inhibitory control. Deletion of one Fxyd1 allele also prevented the increased extracellular potassium (K+) accumulation observed in cerebro-cortical neurons from Mecp2 KO animals in response to the NKA inhibitor ouabain, and rescued the loss of dendritic arborization observed in FC neurons of Mecp2 KO mice. These effects were gene-dose dependent, because the absence of Fxyd1 failed to rescue the MeCP2-dependent deficits, and mimicked the effect of MeCP2 deficiency in wild-type animals. These results indicate that excess of Fxyd1 in the absence of MeCP2 results in deregulation of endogenous K+ conductances functionally associated with NKA and leads to stunted neuronal growth.

Inhibition of Gsk3b Reduces Nfkb1 Signaling and Rescues Synaptic Activity to Improve the Rett Syndrome Phenotype in Mecp2-Knockout Mice

Rett syndrome (RTT) is the second leading cause of mental impairment in girls and is currently untreatable. RTT is caused, in more than 95% of cases, by loss-of-function mutations in the methyl CpG-binding protein 2 gene (MeCP2). We propose here a molecular target involved in RTT: the glycogen synthase kinase-3b (Gsk3b) pathway. Gsk3b activity is deregulated in Mecp2-knockout (KO) mice models, and SB216763, a specific inhibitor, is able to alleviate the clinical symptoms with consequences at the molecular and cellular levels. Invivo, inhibition of Gsk3b prolongs the lifespan of Mecp2-KO mice andreduces motor deficits. At the molecular level, SB216763 rescues dendritic networks and spine density, while inducing changes in the properties ofexcitatory synapses. Gsk3b inhibition can also decrease the nuclear activity of the Nfkb1 pathway and neuroinflammation. Altogether, our findings indicate that Mecp2 deficiency in the RTT mouse model is partially rescued following treatment with SB216763.

A codon-optimized Mecp2 transgene corrects breathing deficits and improves survival in a mouse model of Rett syndrome

Rett syndrome (RTT) is a severe X-linked neurodevelopmental disorder that is primarily caused by mutations in the methyl CpG binding protein 2 gene (MECP2). RTT is the second most prevalent cause of intellectual disability in girls and there is currently no cure for the disease. The finding that the deficits caused by the loss of Mecp2 are reversible in the mouse has bolstered interest in gene therapy as a cure for RTT. In order to assess the feasibility of gene therapy in a RTT mouse model, and in keeping with translational goals, we investigated the efficacy of a self-complementary AAV9 vector expressing a codon-optimized version of Mecp2 (AAV9-MCO) delivered via a systemic approach in early symptomatic Mecp2-deficient (KO) mice. Our results show that AAV9-MCO administered at a dose of 2×1011 viral genome (vg)/mouse was able to significantly increase survival and weight gain, and delay the occurrence of behavioral deficits. Apneas, which are one of the core RTT breathing deficits, were significantly decreased to WT levels in Mecp2 KO mice after AAV9-MCO administration. Semi-quantitative analysis showed that AAV9-MCO administration in Mecp2 KO mice resulted in 10 to 20% Mecp2 immunopositive cells compared to WT animals, with the highest Mecp2 expression found in midbrain regions known to regulate cardio-respiratory functions. In addition, we also found a cell autonomous increase in tyrosine hydroxylase levels in the A1C1 and A2C2 catecholaminergic Mecp2+ neurons in treated Mecp2 KO mice, which may partly explain the beneficial effect of AAV9-MCO administration on apneas occurrence.

Activity and MeCP2-dependent regulation of nNOS levels in enteric neurons.

Rett syndrome (RTT) is a neurological disorder characterized by severe cognitive impairment, motor dyspraxia, and seizures. Rett syndrome arises predominantly from mutations in MECP2, the gene coding for methyl-CpG-binding protein 2 (MeCP2). MeCP2 is an important mediator of synaptic development and is essential in regulating homeostatic synaptic plasticity (HSP) in the brain. In addition to demonstrating central nervous system impairment, RTT patients also suffer from gastrointestinal (GI) dysmotility. We hypothesize that this is due to a similar impairment of plasticity-dependent synaptic function in the enteric nervous system (ENS). We recently reported that MeCP2 is expressed in the ENS, providing evidence that neuronal dysfunction may mediate the GI pathology. Baseline measures of MeCP2-KO vs wild-type (WT) GI neuronal nitric oxide synthase (nNOS) were assessed in tissue samples and in vitro. Experiments were carried out to measure nNOS in baseline vs activated plasticity states in vitro. Functional in vivo studies were carried out to determine whether MeCP2-KO mice reproduced the RTT GI hypomotility. Methyl-CpG-binding protein 2-KO mice reproduced the GI hypomotility seen in RTT. MeCP2-KO GI tissue demonstrated elevated nNOS levels. Cultured WT enteric neurons showed upregulation of nNOS following moderate, prolonged stimulation by hyperkalemia; neurons from MeCP2-KO mice failed to show this nNOS upregulation. MeCP2 is required for proper GI motility and normal nNOS levels. Neuronal nitric oxide synthase imbalances could mediate the GI dysmotility seen in RTT. Disruption of MeCP2-dependent HSP may be the basis for aberrant nNOS levels and hence GI dysmotility in MeCP2-KO and RTT.

CX3CR1 ablation ameliorates motor and respiratory dysfunctions and improves survival of a Rett syndrome mouse model

Rett syndrome (RTT) is a neurodevelopmental disorder caused by loss-of-function mutations in the gene encoding MeCP2, an epigenetic modulator that binds the methyl CpG dinucleotide in target genes to regulate transcription. Previously we and others reported a role of microglia in the pathophysiology of RTT. Because microglia in the Mecp2 knockout (Mecp2KO) mouse model of RTT over-produce neurotoxic mediators glutamate and reactive oxygen species, we hypothesize that blocking neuron–microglia interaction by ablation of CX3CR1, a chemokine receptor expressed in microglia/myeloid cells mediating such interaction by pairing with its neuronal ligand CX3CL1, would ameliorate the RTT-like phenotype in Mecp2KO mice. Here we report that CX3CR1 ablation prolonged the lifespan of Mecp2KO mice from a median survival of 54.5–74days, and significantly improved the body weight gain, symptomatic scores, major respiratory parameters, and motor coordination and performance. CX3CR1 ablation rectified previously identified histological abnormalities in the Mecp2KO brain such as neuronal soma size in hippocampal CA2, and the number, soma size, and process complexity of microglia. Moreover, CX3CR1 ablation enhanced the neurotrophic action of microglia in Mecp2KO mice by producing higher amount of insulin-like growth factor 1. Our data support a role of myeloid cells/microglia in RTT and suggest a novel therapeutic approach for RTT by targeting CX3CR1 with specific antagonists or genetic downregulation.

P198 – 3022: GABAergic dysfunction in neurons derived from induced pluripotent stem cells of patients with Rett syndrome

Objective Induced pluripotent stem cells (iPs cells) are a promising tool for the study of neurological diseases. Disruption of GABAergic activity in Rett Syndrome (RTT) can be related, at least in part, with a failure to complete the GABA functional switch that occurs during normal development, from excitation in immature neurons to inhibition in mature neurons. This switch is mainly mediated by a developmental increase in KCC2 expression, a co-transporter that drives Cl-efflux outside neurons, with the consequent decrease in intracellular Cl-concentration and GABA-mediated hyperpolarization in mature neurons. We documented reduced KCC2 levels in the cerebrospinal fluid of RTT patients and aimed to test GABAergic function in neurons derived from RTT patients' iPs cells. Methods Human skin biopsies were collected in accordance with European and National ethical regulation and IPS cells were generated from fibroblast cells upon infection with a retroviral vector expressing four transcription factors (Oct4, Sox2, Klf4, and Myc). IPs cell lines were obtained from patients carrying MECP2 mutations (R306C and R255X) and controls. Neuronal cortical populations were derived in a monolayer culture system using the dual-SMAD inhibition protocol. Perforated patch recordings were performed in these neurons and GABA-evoked postsynaptic currents were measured to evaluate GABA A receptor equilibrium potencial. Adittionally, we performed molecular studies in a RTT mouse model (Mecp2tm1.1Bird/J). Results Preliminary data indicate that recordings from RTT cells exhibit a GABA A receptor equilibrium potential that is more positive than in recordings from control cells, indicating changes in chloride gradient, characteristic of an immature state. The level of KCC2 protein expression is lower in Mecp2-KO mice when compared to control littermates, as addressed by western blot analysis of 6 week old hippocampi. Conclusion Results form the animal model, iPs cell-based models and cerebrospinal fluid studies suggest a GABAergic dysfunction in RTT, including alterations in KCC2 expression and/or activity.

Twenty-four hour quantitative-EEG and in-vivo glutamate biosensor detects activity and circadian rhythm dependent biomarkers of pathogenesis in Mecp2 null mice.

Mutations in the X-linked gene encoding methyl-CpG-binding protein 2 (Mecp2) cause most cases of Rett syndrome (RTT). Currently there is no cure for RTT. Abnormal EEGs are found in 100% of RTT cases and are associated with severe sleep dysfunction, the cause of which is not well understood. Mice deficient in MeCP2 protein have been studied and characterized for their neuropathological and behavioral deficits to better understand RTT. With the goal to study the non-ictal EEG correlates in symptomatic Mecp2 KO mice (Mecp2tm1.1Bird/y), and determine novel EEG biomarkers of their reported progressive neurodegeneration, we used 24 h video-EEG/EMG with synchronous in-vivo cortical glutamate biosensor in the frontal cortex. We scored the EEG for activity states and spectral analysis was performed to evaluate correlations to the synchronous extracellular glutamate fluctuations underlying Mecp2 inactivation as compared to WT. Significant alterations in sleep structure due to dark cycle-specific long wake states and poor quality of slow-wave sleep were associated with a significant increase in glutamate loads per activity cycle. The dynamics of the activity-state-dependent physiological rise and fall of glutamate indicative of glutamate homeostasis were significantly altered in the KO mice. Colorimetric quantitation of absolute glutamate levels in frontal cortex also indicated the presence of significantly higher levels in KO. This study for the first time found evidence of uncompensated sleep deprivation-like EEG biomarkers that were associated with glutamate homeostatic dysfunction in the Mecp2 KO mice.

A novel DNA-binding feature of MeCP2 contributes to Rett syndrome

GENERAL COMMENTARY article Front. Cell. Neurosci., 09 May 2013Sec. Cellular Neurophysiology Volume 7 - 2013 | https://doi.org/10.3389/fncel.2013.00064

Peripheral administration of brain-derived neurotrophic factor to Rett syndrome animal model: A possible approach for the treatment of Rett syndrome

SummaryRett syndrome (RTT) is a postnatal, severe, disabling neurodevelopmental disorder occurring almost exclusively in females and is the second most common cause for genetic mental retardation in girls. In the majority of cases it is caused by mutations in gene (MECP2) encoding methyl-CpG-binding protein 2. Brain-derived neurotrophic factor (BDNF) is a neurotrophic factor playing a major role in neuronal survival, neurogenesis and plasticity. Animal studies suggested that abnormalities in BDNF homeostasis may contribute to the pathogenesis in Mecp2 null mice, and BDNF administration in the Mecp2 mutant brain led to later onset/slower disease progression, suggesting that increased BDNF in the brain could be therapeutic for this disease. Mature BDNF is a 14 kDa protein that may have poor blood-brain barrier penetrability. However, recent animal studies demonstrated that peripheral administration of BDNF, either by intravenous injection or intranasal delivery, could increase BDNF levels in the brain. Thus it is proposed that peripheral administration of BDNF in the early stage could have therapeutic potential for RTT subjects. Furthermore, the combination use of mannitol may temporarily open the blood-brain barrier and facilitate the entry of BDNF into brain. The potential therapeutic effect of peripheral BDNF administration could be tested in RTT animal models such as Mecp2 KO mice, which may provide a new intervention for this devastating disease.

Corrigenda

The Journal of PhysiologyVolume 589, Issue 15 p. 3897-3897 Free Access Corrigenda This article corrects the following: Remodelling of the respiratory network in a mouse model of Rett syndrome depends on brain-derived neurotrophic factor regulated slow calcium buffering S. L. Mironov, E. Skorova, N. Hartelt, L. A. Mironova, M. T. Hasan, S. Kügler, Volume 587Issue 11The Journal of Physiology pages: 2473-2485 First Published online: June 3, 2009 First published: 17 June 2011 https://doi.org/10.1113/jphysiol.2011.212191AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat The article by Mironov et al. (2009) contained an error in Fig. 7B. Figure 7 should have appeared as follows. It should be noted that the error does not alter results or discussion in the text. Figure 7Open in figure viewerPowerPoint Retraction of neuronal processes after global calcium increases A, images of the respiratory network in wild-type and MeCP2 KO mice at P28 obtained before and 60 min after application of the agents which produced long-lasting calcium increases – a chemical hypoxia (200 μm KCN) in control and after pretreatment with 20 ng ml−1 BDNF for 20 min, 1 μm thapsigargin and 1 μm CCCP. The positions of some retracted processes are indicated by arrowheads. B, correlations between retractions of the processes and measured peak [Ca2+]i. Straight lines show linear regression of the data. References Mironov SL, Skorova E, Hartelt N, Mironova LA, Hasan MT & Kügler S (2009). Remodelling of the respiratory network in a mouse model of Rett syndrome depends on brain-derived neurotrophic factor regulated slow calcium buffering. J Physiol 587, 2473– 2485. Volume589, Issue15August 2011Pages 3897-3897 FiguresReferencesRelatedInformation

Mecp2-Null Mice Provide New Neuronal Targets for Rett Syndrome

BackgroundRett syndrome (RTT) is a complex neurological disorder that is one of the most frequent causes of mental retardation in women. A great landmark in research in this field was the discovery of a relationship between the disease and the presence of mutations in the gene that codes for the methyl-CpG binding protein 2 (MeCP2). Currently, MeCP2 is thought to act as a transcriptional repressor that couples DNA methylation and transcriptional silencing. The present study aimed to identify new target genes regulated by Mecp2 in a mouse model of RTT.Methodology/Principal FindingsWe have compared the gene expression profiles of wild type (WT) and Mecp2-null (KO) mice in three regions of the brain (cortex, midbrain, and cerebellum) by using cDNA microarrays. The results obtained were confirmed by quantitative real-time PCR. Subsequent chromatin immunoprecipitation assays revealed seven direct target genes of Mecp2 bound in vivo (Fkbp5, Mobp, Plagl1, Ddc, Mllt2h, Eya2, and S100a9), and three overexpressed genes due to an indirect effect of a lack of Mecp2 (Irak1, Prodh and Dlk1). The regions bound by Mecp2 were always methylated, suggesting the involvement of the methyl-CpG binding domain of the protein in the mechanism of interaction.ConclusionsWe identified new genes that are overexpressed in Mecp2-KO mice and are excellent candidate genes for involvement in various features of the neurological disease. Our results demonstrate new targets of MeCP2 and provide us with a better understanding of the underlying mechanisms of RTT.