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

Article (PDF Available)inNature Neuroscience 12(3):311-7 · April 2009with39 Reads
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).


    • "This was repeated once and then sections were washed 3 times with 0.1 M phosphate buffer. Sections were then immunostained with a rabbit antibody directed against the C-terminus of Mecp2 (a generous gift from M. Greenberg Harvard Medical School) (Ballas et al., 2009 ) and a chicken antibody against Iba-1 (Abcam, Cambridge, MA), overnight at room temperature . Sections were then washed and HRP-conjugated rabbit and Alexa fluor-conjugated rat antibodies were added to the sections for 1–2 hr at room temperature. "
    [Show abstract] [Hide abstract] ABSTRACT: Microglia, the resident CNS macrophages, have been implicated in the pathogenesis of Rett Syndrome (RTT), an X-linked neurodevelopmental disorder. However, the mechanism by which microglia contribute to the disorder is unclear and recent data suggest that microglia do not play a causative role. Here, we use the retinogeniculate system to determine if and how microglia contribute to pathogenesis in a RTT mouse model, the Mecp2 null mouse (Mecp2tm1.1Bird/y). We demonstrate that microglia contribute to pathogenesis by excessively engulfing, thereby eliminating, presynaptic inputs at end stages of disease (≥P56 Mecp2 null mice) concomitant with synapse loss. Furthermore, loss or gain of Mecp2 expression specifically in microglia (Cx3cr1CreER;Mecp2fl/yor Cx3cr1CreER; Mecp2LSL/y) had little effect on excessive engulfment, synapse loss, or phenotypic abnormalities. Taken together, our data suggest that microglia contribute to end stages of disease by dismantling neural circuits rendered vulnerable by loss of Mecp2 in other CNS cell types. DOI:
    Full-text · Article · Jul 2016
    • "This is also accompanied by neurotoxicity due to excessive glutamate release from microglia (Maezawa and Jin, 2010 ). Moreover , MeCP2-null astrocytes are unable to support normal dendritic morphology in wild-type hippocampal neurons (Ballas et al., 2009 ). In addition, MeCP2-null neurons have abnormal dendritic and axonal development (Larimore et al., 2009), and MeCP2-deficient GABAergic neurons show reduced inhibitory quantal size and decreased expression of GAD (Chao et al., 2010). "
    [Show abstract] [Hide abstract] ABSTRACT: Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social and communication impairments, as well as repetitive and restrictive behaviors. The phenotypic heterogeneity of ASD has made it overwhelmingly difficult to determine the exact etiology and pathophysiology underlying the core symptoms, which are often accompanied by comorbidities such as hyperactivity, seizures, and sensorimotor abnormalities. To our benefit, the advent of animal models has allowed us to assess and test diverse risk factors of ASD, both genetic and environmental, and measure their contribution to the manifestation of autistic symptoms. At a broader scale, rodent models have helped consolidate molecular pathways and unify the neurophysiological mechanisms underlying each one of the various etiologies. This approach will potentially enable the stratification of ASD into clinical, molecular, and neurophenotypic subgroups, further proving their translational utility. It is henceforth paramount to establish a common ground of mechanistic theories from complementing results in preclinical research. In this review, we cluster the ASD animal models into lesion and genetic models and further classify them based on the corresponding environmental, epigenetic and genetic factors. Finally, we summarize the symptoms and neuropathological highlights for each model and make critical comparisons that elucidate their clinical and neurobiological relevance.
    Full-text · Article · May 2016
    • "The development of disease is attributed to a loss-of-function mutation of the brain-specific methyl- CpG-binding protein MeCP2 [56, 152]. The lack of MeCP2 leads to the pathological up-regulation of target genes in mature neurons leading to enhanced synaptic inhibition in the cortex [153], affecting as well the normal functioning of glial cells [154][155]. More specifically, the RTT phenotype is characterized by abnormalities in dendritic branching [156], spine maturation [157], altered excitatory synaptic plasticity [152] and increased inhibition [153]. "
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