Ballas N, Lioy DT, Grunseich C, Mandel G. Non-cell autonomous influence of MeCP2-deficient glia on neuronal dendritic morphology. Nat Neurosci 12: 311-317

Howard Hughes Medical Institute, Department of Neurobiology and Behavior, State University of New York, Stony Brook, New York 11794, USA. (
Nature Neuroscience (Impact Factor: 16.1). 04/2009; 12(3):311-7. DOI: 10.1038/nn.2275
Source: PubMed


The neurodevelopmental disorder Rett syndrome (RTT) is caused by sporadic mutations in the transcriptional factor methyl-CpG-binding protein 2 (MeCP2). Although it is thought that the primary cause of RTT is cell autonomous, resulting from a lack of functional MeCP2 in neurons, whether non-cell autonomous factors contribute to the disease is unknown. We found that the loss of MeCP2 occurs not only in neurons but also in glial cells of RTT brains. Using an in vitro co-culture system, we found that mutant astrocytes from a RTT mouse model, and their conditioned medium, failed to support normal dendritic morphology of either wild-type or mutant hippocampal neurons. Our studies suggest that astrocytes in the RTT brain carrying MeCP2 mutations have a non-cell autonomous effect on neuronal properties, probably as a result of aberrant secretion of soluble factor(s).

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Available from: Christopher Grunseich, Jul 31, 2014
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    • "The loss of KF GABAergic innervation that we observed in Mecp2 +/− mice may involve contribution of mutant glia in a non-cell-autonomous manner. Mecp2 is expressed in astroglia (Yasui et al., 2013; Forbes- Lorman et al., 2014), and loss of MECP2 impairs astrocytic glutamate clearance (Okabe et al., 2012) promoting dendritic damage in neurones (Ballas et al., 2009; Maezawa & Jin, 2010). In the present study, we observed that loss of GABAergic terminal projections depended on local non-cell-autonomous and cell-autonomous mechanisms, with the latter contributing to a lesser degree. "
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    ABSTRACT: Central apnoeas and respiratory irregularity are a common feature in Rett syndrome (RTT), a neurodevelopmental disorder most often caused by mutations in the methyl-CpG-binding protein 2 gene (MECP2). We used a MECP2 deficient mouse model of RTT as a strategy to obtain insights into the neurobiology of the disease and into mechanisms essential for respiratory rhythmicity during normal breathing. Previously, we showed that, systemic administration of a GABA reuptake blocker in MECP2 deficient mice markedly reduced the occurrence of central apnoeas. Further, we found that, during central apnoeas, post-inspiratory drive (adductor motor) to the upper airways was enhanced in amplitude and duration in Mecp2 heterozygous female mice. Since pontine Kölliker-Fuse (KF) region drives post-inspiration, suppresses inspiration, and can reset the respiratory oscillator phase, we hypothesized that synaptic inhibition in this area is essential for respiratory rhythm regularity. In this study, we found that: (i) Mecp2 heterozygous mice show deficiency of GABA perisomatic bouton-like puncta and processes in the KF; (ii) blockade of GABA reuptake in the KF of RTT mice reduced breathing irregularity; (iii) conversely, blockade of GABAA receptors in the KF of healthy rats mimicked the RTT respiratory phenotype of recurrent central apnoeas and prolonged post-inspiratory activity. Our results show that reductions in synaptic inhibition within the KF induce rhythm irregularity whereas boosting GABA transmission reduces respiratory arrhythmia in a murine model of RTT. Our data suggest that manipulation of synaptic inhibition in KF may be a clinically important strategy for alleviating the life threatening respiratory disorders in RTT. This article is protected by copyright. All rights reserved.
    The Journal of Physiology 10/2015; DOI:10.1113/JP270966 · 5.04 Impact Factor
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    • "The medium was then collected from the 5-week-old astrocyte cultures and centrifuged at 1000 g for 5 min. The supernatant of the medium was used for ELISA to measure the levels of soluble Ab40 and Ab42 released from cultured astrocytes or used to treat hippocampal neurons (2 ml medium containing 1 ml ACM) as previously described (Ballas et al., 2009). "
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    ABSTRACT: Studies have implicated astrocytic dysfunction in Alzheimer's disease (AD). However, the role of astrocytes in the pathophysiology and treatment of the disease is poorly characterized. Here, we identified astrocytes as independent key factors involved in several Alzheimer-like phenotypes in an APP/PS1 mouse model, including amyloid pathology, altered neuronal and synaptic properties, and impaired cognition. In vitro astrocytes from APP/PS1 mice induced synaptotoxicity as well as reduced dendritic complexity and axonal branching of hippocampal neurons. These astrocytes produced high levels of soluble β-amyloid (Aβ) which could be significantly inhibited by fluoxetine (FLX) via activating serotonin 5-HT2 receptors. FLX could also protect hippocampal neurons against astrocyte-induced neuronal damage in vitro. In the same APP/PS1 mice, FLX inhibited activation of astrocytes, lowered Aβ products, ameliorated neurotoxicity, and improved behavioral performance. These findings may provide a basis for the clinical application of FLX in patients, and may also lay the groundwork for exploration of other novel astrocyte-based therapies of AD. GLIA 2015.
    Glia 10/2015; DOI:10.1002/glia.22926 · 6.03 Impact Factor
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    • "In vitro experiments by Ballas et al . ( 2009 ) found that hippocampal neurons cultured with MeCP2 deleted astrocytes or their conditioned medium , failed to show normal dendritic development . Impaired dendrite formation by astrocytic MeCP2 occurs independent of the presence of neural MeCP2 , suggesting that dysregulation of astrocytic soluble factors induced by MeCP2 deletion may"
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    ABSTRACT: Astrocytes play an essential role in supporting brain functions in physiological and pathological states. Modulation of their pathophysiological responses have beneficial actions on nerve tissue injured by brain insults and neurodegenerative diseases, therefore astrocytes are recognized as promising targets for neuroprotective drugs. Recent investigations have identified several astrocytic mechanisms for modulating synaptic transmission and neural plasticity. These include altered expression of transporters for neurotransmitters, release of gliotransmitters and neurotrophic factors, and intercellular communication through gap junctions. Investigation of patients with mental disorders shows morphological and functional alterations in astrocytes. According to these observations, manipulation of astrocytic function by gene mutation and pharmacological tools reproduce mental disorder-like behavior in experimental animals. Some drugs clinically used for mental disorders affect astrocyte function. As experimental evidence shows their role in the pathogenesis of mental disorders, astrocytes have gained much attention as drug targets for mental disorders. In this paper, I review functional alterations of astrocytes in several mental disorders including schizophrenia, mood disorder, drug dependence, and neurodevelopmental disorders. The pharmacological significance of astrocytes in mental disorders is also discussed.
    Frontiers in Cellular Neuroscience 07/2015; 9:261. DOI:10.3389/fncel.2015.00261 · 4.29 Impact Factor
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