Excitation and Inhibition Imbalance in Rett Syndrome

Li, Wei

doi:10.3389/fnins.2022.825063

Cited by 19 publications

(19 citation statements)

References 195 publications

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“…Through this study, three synaptic pathways enriched in the skyblue module were identified, namely the cholinergic, glutamatergic, and GABAergic pathways. A loss of excitation/inhibition (E/I) balance in the neural circuit is a major hallmark of RTT pathology, causing many neurological symptoms, such as loss of purposeful hand movements, impaired motor coordination, breathing irregularities, and seizures, amongst others [ 10 ]. This loss of E/I balance is caused by MeCP2 deficiency, leading to a dysregulation of the glutamatergic and GABAergic pathways.…”

Section: Discussionmentioning

confidence: 99%

“…MeCP2 also acts as a transcription activator to regulate gene expression by either long-range chromatin remodeling or by regulating RNA splicing [ 7 , 8 , 9 ]. MeCP2-deficiency leads to an excitation/inhibition (E/I) imbalance in the brain and is recognized as the leading cellular and synaptic hallmark of the disorder resulting in stereotypic hand movements, impaired motor coordination, breathing irregularities, seizures, and learning/memory dysfunctions [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

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Meta-Analysis Identifies BDNF and Novel Common Genes Differently Altered in Cross-Species Models of Rett Syndrome

Haase

Singh

Gloss

et al. 2022

IJMS

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Rett syndrome (RTT) is a rare disorder and one of the most abundant causes of intellectual disabilities in females. Single mutations in the gene coding for methyl-CpG-binding protein 2 (MeCP2) are responsible for the disorder. MeCP2 regulates gene expression as a transcriptional regulator as well as through epigenetic imprinting and chromatin condensation. Consequently, numerous biological pathways on multiple levels are influenced. However, the exact molecular pathways from genotype to phenotype are currently not fully elucidated. Treatment of RTT is purely symptomatic as no curative options for RTT have yet to reach the clinic. The paucity of this is mainly due to an incomplete understanding of the underlying pathophysiology of the disorder with no clinically useful common disease drivers, biomarkers, or therapeutic targets being identified. With the premise of identifying universal and robust disease drivers and therapeutic targets, here, we interrogated a range of RTT transcriptomic studies spanning different species, models, and MECP2 mutations. A meta-analysis using RNA sequencing data from brains of RTT mouse models, human post-mortem brain tissue, and patient-derived induced pluripotent stem cell (iPSC) neurons was performed using weighted gene correlation network analysis (WGCNA). This study identified a module of genes common to all datasets with the following ten hub genes driving the expression: ATRX, ADCY7, ADCY9, SOD1, CACNA1A, PLCG1, CCT5, RPS9, BDNF, and MECP2. Here, we discuss the potential benefits of these genes as therapeutic targets.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Meta-Analysis Identifies BDNF and Novel Common Genes Differently Altered in Cross-Species Models of Rett Syndrome

Haase

Singh

Gloss

et al. 2022

IJMS

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“…34,35 Imbalance of excitatory/ inhibitory circuits may be one of the important causes of RTT. 36 In GABAergic neurons derived from the RTT-iPSCs, GABAergic circuit disruption and decrease of acetylated α-tubulin were also found.…”

Section: Cdkl5mentioning

confidence: 94%

“…This result may be caused by the downregulated expression of neuron‐specific membrane transporter K + /Cl + cotransporter (KCC2) mediated by RE1‐silencing transcription factor (REST), a neuronal gene inhibitor in RTT, which is essential for maintaining excitatory balance in the brain 34,35 . Imbalance of excitatory/inhibitory circuits may be one of the important causes of RTT 36 . In GABAergic neurons derived from the RTT‐iPSCs, GABAergic circuit disruption and decrease of acetylated α‐tubulin were also found 37 …”

Section: Research Progress On the Pathogenesis Of Rtt Using Cell Modelsmentioning

confidence: 99%

Advances in the pathogenesis of Rett syndrome using cell models

Lü

陈

Wang

2022

Anim Models and Exp Med

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Rett syndrome (RTT) is a neurodevelopmental disorder with certain symptoms of autism spectrum disorder (ASD). [1][2][3][4] Methyl-CpG binding protein 2 (MECP2) was the first identified ASD-causing gene.Mutations of the MECP2 gene contributed most to the occurrence of RTT. Several other genes, such as CDKL5 and FOXG1, are also identified as RTT-causing genes that lead to atypical RTT. [5][6][7][8] Evidence shows that several neurodevelopmental disorders are related to dysfunction of MeCP2 protein expression. 9 Therefore, the research progress of pathogenesis and treatment on RTT might be a wide reference to other ASD diseases. In this review, we focus mainly on the progress of MECP2 mutant RTT.Research on RTT has usually been based on patients or animal models. However, owing to ethical concerns, it is difficult to draw materials from clinical subjects, and animal models can simulate only partial phenotypes of clinical patients. Therefore, it is not enough to conduct in-depth studies in these ways. It is necessary to use cellular models to study the comparatively systematic, complete mechanisms.Here we reviewed the important progress in the pathogenesis of RTT using cell models.

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“…Through this study, three synaptic pathways enriched in the skyblue module were identified, namely the cholinergic, glutamatergic, and GABAergic pathways. A loss of excitation/inhibition (E/I) balance in the neural circuit is a major hallmark of RTT pathology, causing many neurological symptoms such as loss of purposeful hand movements, impaired motor coordination, breathing irregularities and seizures amongst others [55]. This loss of E/I balance is caused by MeCP2 deficiency leading to dysregulation of the glutamatergic and GABAergic pathways, furthermore downstream genes affected in RTT such as BDNF play an important role influencing neurotransmission activity.…”

Section: Meta-analysis Shows Commonly Dysregulated Synaptic Pathwaysmentioning

confidence: 99%

Meta-Analysis Identifies Novel Common Genes Differently Altered in Cross-Species Models of Rett Syndrome

Haase¹,

Singh²,

Gloss³

et al. 2022

Preprint

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Rett syndrome (RTT) is a rare disease and one of the most abundant causes for intellectual disa-bilities in females. Single mutations in the gene coding for methyl-CpG-binding protein 2 (MECP2), are responsible for the disease. MeCP2 regulates gene expression as a transcriptional regulator as well as through epigenetic imprinting and chromatin condensation. Consequently, numerous biological pathways on multiple levels are influenced however, the exact molecular pathways from genotype to phenotype are currently not fully elucidated. Treatment of RTT is purely symptomatic where no curative options for RTT have yet to reach the clinic. The paucity of this is mainly due to an incomplete understanding of the underlying pathophysiology of the dis-order with no clinically useful common disease drivers, biomarkers or therapeutic targets being identified. With the premise of identifying universal and robust disease drivers and therapeutic targets, here we interrogated a range of RTT transcriptomic studies spanning different species, models and MECP2 mutations. A meta-analysis using RNA sequencing data from brains of RTT mouse models human post-mortem brain tissue and patient-derived induced pluripotent stem cells (iPSC) neurons was performed using Weighted Gene Correlation Network Analysis (WGC-NA). This study identified a module of genes common to all datasets with the following ten hub genes driving the expression ATRX, ADCY7, ADCY9, SOD1, CACNA1A, PLCG1, CCT5, RPS9, BDNF and MECP2. Here we discuss the potential benefits of these genes as therapeutic targets.

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Excitation and Inhibition Imbalance in Rett Syndrome

Cited by 19 publications

References 195 publications

Meta-Analysis Identifies BDNF and Novel Common Genes Differently Altered in Cross-Species Models of Rett Syndrome

Meta-Analysis Identifies BDNF and Novel Common Genes Differently Altered in Cross-Species Models of Rett Syndrome

Advances in the pathogenesis of Rett syndrome using cell models

Meta-Analysis Identifies Novel Common Genes Differently Altered in Cross-Species Models of Rett Syndrome

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