Article

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

ABSTRACT

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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    • "More recent studies have shown that RTT is not exclusively a neuronal disease. Despite the low level of MeCP2 expression in astroglia, oligodendroglia and microglia[12,13], conditionally Mecp2 loss in brain non-neuronal cells detrimentally influences dendritic integrity, synapses and protein expression in neurons[12,14,15]. Availability of many RTT mouse models[16]contributed to disentangle MeCP2 functions and demonstrate that many RTT symptoms can be reverted by postnatal reactivation of MeCP2 expression[17]. "
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    ABSTRACT: Mecp2 null mice model Rett syndrome (RTT) a human neurological disorder affecting females after apparent normal pre- and peri-natal developmental periods. Neuroanatomical studies in cerebral cortex of RTT mouse models revealed delayed maturation of neuronal morphology and autonomous as well as non-cell autonomous reduction in dendritic complexity of postnatal cortical neurons. However, both morphometric parameters and high-resolution expression profile of cortical neurons at embryonic developmental stage have not yet been studied. Here we address these topics by using embryonic neuronal primary cultures from Mecp2 loss of function mouse model. We show that embryonic primary cortical neurons of Mecp2 null mice display reduced neurite complexity possibly reflecting transcriptional changes. We used RNA-sequencing coupled with a bioinformatics comparative approach to identify and remove the contribution of variable and hard to quantify non-neuronal brain cells present in our in vitro cell cultures. Our results support the need to investigate both Mecp2 morphological as well as molecular effect in neurons since prenatal developmental stage, long time before onset of Rett symptoms.
    Full-text · Article · Feb 2016 · BMC Bioinformatics
    • "Does not recapitulate real physiological state, many effectors are only released upon activation or Cell density and coating is crucial; media composition can alter the outcome of the experiment; dependingWang (2012), Maezawa and Jin (2010),Ballas et al. (2009),Williams (2014)handle than their human counterparts and can be sufficient to prove the effect of a known disease causing mutation. If no mouse model exists, the gene of interest can be expressed via lentiviral transduction of wild type primary rodent glia or neurons to study the impact on their survival or communication . "
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    ABSTRACT: For the past century, research on neurological disorders has largely focused on the most prominently affected cell types – the neurons. However, with increasing knowledge of the diverse physiological functions of glial cells, their impact on these diseases has become more evident. Thus, many conditions appear to have more complex origins than initially thought. Since neurological pathologies are often sporadic with unknown etiology, animal models are difficult to create and might only reflect a small portion of patients in which a mutation in a gene has been identified. Therefore, reliable in vitro systems to studying these disorders are urgently needed. They might be a pre-requisite for improving our understanding of the disease mechanisms as well as for the development of potential new therapies. In this review, we will briefly summarize the function of different glial cell types in the healthy central nervous system (CNS) and outline their implication in the development or progression of neurological conditions. We will then describe different types of culture systems to model non-cell autonomous interactions in vitro and evaluate advantages and disadvantages.
    No preview · Article · Jan 2016 · Brain research
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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.
    Full-text · Article · Oct 2015 · Glia
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