Loss of MeCP2 in immature neurons leads to impaired network integration

Sun, Yi; Gao, Yu; Tidei, Joseph J; Hoang, Johnson T.; Wagner, Daniel J.; Zhao, Xinyu

doi:10.1093/hmg/ddy338

Cited by 31 publications

(26 citation statements)

References 58 publications

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“…Rarer variants are associated with mutations in CDKL5 (Cyclin-Dependent Kinase-Like 5), a regulator of MeCP2, and FOXG1 [ 11 , 12 ]. Dysfunction of the MECP2 gene results in impaired brain development, neuronal structure and synaptic function [ 13 ], with consequent abnormalities in network function [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

Functional Network Mapping Reveals State-Dependent Response to IGF1 Treatment in Rett Syndrome

et al. 2020

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Rett Syndrome (RTT) is a neurodevelopmental disorder associated with mutations in the gene MeCP2, which is involved in the development and function of cortical networks. The clinical presentation of RTT is generally severe and includes developmental regression and marked neurologic impairment. Insulin-Like growth factor 1 (IGF1) ameliorates RTT-relevant phenotypes in animal models and improves some clinical manifestations in early human trials. However, it remains unclear whether IGF1 treatment has an impact on cortical electrophysiology in line with MeCP2’s role in network formation, and whether these electrophysiological changes are related to clinical response. We performed clinical assessments and resting-state electroencephalogram (EEG) recordings in eighteen patients with classic RTT, nine of whom were treated with IGF1. Among the treated patients, we distinguished those who showed improvements after treatment (responders) from those who did not show any changes (nonresponders). Clinical assessments were carried out for all individuals with RTT at baseline and 12 months after treatment. Network measures were derived using statistical modelling techniques based on interelectrode coherence measures. We found significant interaction between treatment groups and timepoints, indicating an effect of IGF1 on network measures. We also found a significant effect of responder status and timepoint, indicating that these changes in network measures are associated with clinical response to treatment. Further, we found baseline variability in network characteristics, and a machine learning model using these measures applied to pretreatment data predicted treatment response with 100% accuracy (100% sensitivity and 100% specificity) in this small patient group. These results highlight the importance of network pathology in RTT, as well as providing preliminary evidence for the potential of network measures as tools for the characterisation of disease subtypes and as biomarkers for clinical trials.

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Section: Introductionmentioning

confidence: 99%

Functional Network Mapping Reveals State-Dependent Response to IGF1 Treatment in Rett Syndrome

et al. 2020

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“…In rodents, adult hippocampal neurogenesis is critical for the regulation of anxiety and depression-like behaviour as well as for hippocampus-dependent learning and memory [ 29 ]. Notably, impaired adult hippocampal neurogenesis was found to contribute to cognitive deficits in preclinical models for autism-spectrum disorders and intellectual disability [ 30 – 33 ].…”

Section: Introductionmentioning

confidence: 99%

Enriched environment ameliorates adult hippocampal neurogenesis deficits in Tcf4 haploinsufficient mice

et al. 2020

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Background Transcription factor 4 (TCF4) has been linked to human neurodevelopmental disorders such as intellectual disability, Pitt-Hopkins Syndrome (PTHS), autism, and schizophrenia. Recent work demonstrated that TCF4 participates in the control of a wide range of neurodevelopmental processes in mammalian nervous system development including neural precursor proliferation, timing of differentiation, migration, dendritogenesis and synapse formation. TCF4 is highly expressed in the adult hippocampal dentate gyrus – one of the few brain regions where neural stem / progenitor cells generate new functional neurons throughout life. Results We here investigated whether TCF4 haploinsufficiency, which in humans causes non-syndromic forms of intellectual disability and PTHS, affects adult hippocampal neurogenesis, a process that is essential for hippocampal plasticity in rodents and potentially in humans. Young adult Tcf4 heterozygote knockout mice showed a major reduction in the level of adult hippocampal neurogenesis, which was at least in part caused by lower stem/progenitor cell numbers and impaired maturation and survival of adult-generated neurons. Interestingly, housing in an enriched environment was sufficient to enhance maturation and survival of new neurons and to substantially augment neurogenesis levels in Tcf4 heterozygote knockout mice. Conclusion The present findings indicate that haploinsufficiency for the intellectual disability- and PTHS-linked transcription factor TCF4 not only affects embryonic neurodevelopment but impedes neurogenesis in the hippocampus of adult mice. These findings suggest that TCF4 haploinsufficiency may have a negative impact on hippocampal function throughout adulthood by impeding hippocampal neurogenesis.

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“…We demonstrate that this assay allows to perform phenotypical drug screening for RTT dendritic atrophy, using High Content Imaging techniques and an open-source software to analyze neuronal morphology. www.nature.com/scientificreports www.nature.com/scientificreports/ Previous in vitro mouse models reproducing the developmental deficits of the Rett syndrome were developed using high seeding cell-density in the range of 600-800 cells/mm 2 in 24-well plates 14,27,[30][31][32] . Although a variety of cell-seeding densities ranging from 640 to 40 cells/mm 2 are currently in use [33][34][35] , the available literature on phenotypic drug screening suggests that to perform a reliable measure of cellular morphology using automated image analysis tools, the cellular density should be low 18,36 .…”

Section: Discussionmentioning

confidence: 99%

In vitro modeling of dendritic atrophy in Rett syndrome: determinants for phenotypic drug screening in neurodevelopmental disorders

Nerli

Roggero

Baj

et al. 2020

Sci Rep

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Dendritic atrophy, defined as the reduction in complexity of the neuronal arborization, is a hallmark of several neurodevelopmental disorders, including Rett Syndrome (RTT). RTT, affecting 1:10,000 girls worldwide, is mainly caused by mutations in the MECP2 gene and has no cure. We describe here an in vitro model of dendritic atrophy in Mecp2 −/y mouse hippocampal primary cultures, suitable for phenotypic drug-screening. Using High-content imaging techniques, we systematically investigated the impact of culturing determinants on several parameters such as neuronal survival, total dendritic length, dendritic endpoints, soma size, cell clusterization, spontaneous activity. Determinants included cell-seeding density, glass or polystyrene substrates, coating with poly-ornithine with/without Matrigel and miniaturization from 24 to 96-half surface multiwell plates. We show that in all plate-sizes at densities below 320 cells/mm 2 , morphological parameters remained constant while spontaneous network activity decreased according to the cell-density. Mecp2 −/y neurons cultured at 160 cells/mm 2 density in 96 multiwell plates, displayed significant dendritic atrophy and showed a marked increase in dendritic length following treatment with Brain-derived neurotrophic factor (BDNF) or Mirtazapine. in conclusion, we have established a phenotypic assay suitable for fast screening of hundreds of compounds, which may be extended to other neurodevelopmental diseases with dendritic atrophy.Dendritic atrophy, defined as the reduction in branching complexity of neuronal dendritic processes, is a typical hallmark of several neurodevelopmental disorders 1-4 . With an incidence of 1:10,000 newborn girls, Rett syndrome (RTT) is one of the most common neurodevelopmental diseases with mental retardation in females 5 . In 90-95% of cases, the disease is caused by sporadic mutations in the MECP2 gene 6 . RTT is characterized by a period of early normal development followed by a regression phase, leading to loss of speech and acquired motor skills, presence of stereotypical hand movements, seizures and microcephaly 6 . Presently, there is no cure for Rett syndrome.Due to microcephaly, the brains of RTT patients show more closely packed neurons 7 and reduced dendritic complexity has been described in cerebral cortex, hypothalamus and hippocampus [8][9][10] . The dendritic atrophy observed in the cortex of RTT patients has been related to dysfunctions of neural networks and intellectual disability 9 , similarly to other neurodevelopmental disorders such as Fragile-X syndrome and Down syndrome 1,7 . Accordingly, modelling dendritic atrophy for these diseases is extremely important.Notably, in mouse models for Rett syndrome, reduced brain dimensions and dendritic atrophy has been found in the same brain regions as in humans 11,12 . We previously showed that in vivo treatment of Mecp2 −/y mice with the antidepressant Mirtazapine was able to rescue cortical thickness, neuronal soma area and apical dendrites diameter counteracting breathing abnorma...

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Loss of MeCP2 in immature neurons leads to impaired network integration

Cited by 31 publications

References 58 publications

Functional Network Mapping Reveals State-Dependent Response to IGF1 Treatment in Rett Syndrome

Functional Network Mapping Reveals State-Dependent Response to IGF1 Treatment in Rett Syndrome

Enriched environment ameliorates adult hippocampal neurogenesis deficits in Tcf4 haploinsufficient mice

In vitro modeling of dendritic atrophy in Rett syndrome: determinants for phenotypic drug screening in neurodevelopmental disorders

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