MeCP2 Controls Excitatory Synaptic Strength by Regulating Glutamatergic Synapse Number

Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA.
Neuron (Impact Factor: 15.98). 11/2007; 56(1):58-65. DOI: 10.1016/j.neuron.2007.08.018
Source: PubMed

ABSTRACT MeCP2 is a transcriptional repressor critical for normal neurological function. Prior studies demonstrated that either loss or doubling of MeCP2 results in postnatal neurodevelopmental disorders. To understand the impact of MeCP2 expression on neuronal function, we studied the synaptic properties of individual neurons from mice that either lack or express twice the normal levels of MeCP2. Hippocampal glutamatergic neurons that lack MeCP2 display a 46% reduction in synaptic response, whereas neurons with doubling of MeCP2 exhibit a 2-fold enhancement in synaptic response. Further analysis shows that these changes were primarily due to the number of synapses formed. These results reveal that MeCP2 is a key rate-limiting factor in regulating glutamatergic synapse formation in early postnatal development and that changes in excitatory synaptic strength may underlie global network alterations in neurological disorders due to altered MeCP2 levels.

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Available from: Christian Rosenmund, Jan 13, 2014
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    • "Do neurotransmitter switches contribute to neurological disorders? Mutations in genes involved in the plasticity of synaptic strength are associated with several illnesses (Chao et al., 2007; Fromer et al., 2014; La Montanara et al., 2015). Similarly, sustained exposure to stimuli that drive transmitter switching may contribute to these conditions. "
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    ABSTRACT: Among the many forms of brain plasticity, changes in synaptic strength and changes in synapse number are particularly prominent. However, evidence for neurotransmitter respecification or switching has been accumulating steadily, both in the developing nervous system and in the adult brain, with observations of transmitter addition, loss, or replacement of one transmitter with another. Natural stimuli can drive these changes in transmitter identity, with matching changes in postsynaptic transmitter receptors. Strikingly, they often convert the synapse from excitatory to inhibitory or vice versa, providing a basis for changes in behavior in those cases in which it has been examined. Progress has been made in identifying the factors that induce transmitter switching and in understanding the molecular mechanisms by which it is achieved. There are many intriguing questions to be addressed. Copyright © 2015 Elsevier Inc. All rights reserved.
    Neuron 06/2015; 86(5):1131-1144. DOI:10.1016/j.neuron.2015.05.028 · 15.98 Impact Factor
    • "Altogether, these conditional animal models indicate that MeCP2 must play a role in the maintenance of brain functionality at post-natal ages. On the contrary, the investigation of the possible roles played by Mecp2 during embryonic development has been largely neglected , although it is now generally accepted that subtle but consistent impairments are present even at early post-natal ages, when typical symptoms are not yet overt (Nomura 2005; Picker et al. 2006; Chao et al. 2007; Santos et al. 2007; Fehr et al. 2011). Moreover, as already alluded, hemizygous MECP2 male patients display a severe pathological condition as early as at birth (Schüle et al. 2008; Fu et al. 2014), while MeCP2 null neurons derived from induced pluripotent stem cells (iPSCs) display defective structural and functional maturation (Marchetto et al. 2010; Okabe et al. 2010; Kim et al. 2011; Li et al. 2011; Farra et al. 2012). "
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    ABSTRACT: MeCP2 is associated with several neurological disorders; of which, Rett syndrome undoubtedly represents the most frequent. Its molecular roles, however, are still unclear, and data from animal models often describe adult, symptomatic stages, while MeCP2 functions during embryonic development remain elusive. We describe the pattern and timing of Mecp2 expression in the embryonic neocortex highlighting its low but consistent expression in virtually all cells and show the unexpected occurrence of transcriptional defects in the Mecp2 null samples at a stage largely preceding the onset of overt symptoms. Through the deregulated expression of ionic channels and glutamatergic receptors, the lack of Mecp2 during early neuronal maturation leads to the reduction in the neuronal responsiveness to stimuli. We suggest that such features concur to morphological alterations that begin affecting Mecp2 null neurons around the perinatal age and become evident later in adulthood. We indicate MeCP2 as a key modulator of the transcriptional mechanisms regulating cerebral cortex development. Neurological phenotypes of MECP2 patients could thus be the cumulative result of different adverse events that are already present at stages when no obvious signs of the pathology are evident and are worsened by later impairments affecting the central nervous system during maturation and maintenance of its functionality. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail:
    Cerebral Cortex 05/2015; DOI:10.1093/cercor/bhv078 · 8.67 Impact Factor
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    • "Commonly used strains of Mecp2 KO mice have impaired dendritic complexity [115] [116] and lower dendritic spine density [117] [118] [119] [120] as well as a lack of mushroom spines in cortical and hippocampal neurons [121] [122]. "
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    ABSTRACT: The activity-dependent structural and functional plasticity of dendritic spines has led to the long-standing belief that these neuronal compartments are the subcellular sites of learning and memory. Of relevance to human health, central neurons in several neuropsychiatric illnesses, including autism related disorders, have atypical numbers and morphologies of dendritic spines. These so-called dendritic spine dysgeneses found in individuals with autism related disorders are consistently replicated in experimental mouse models. Dendritic spine dysgenesis reflects the underlying synaptopathology that drives clinically relevant behavioral deficits in experimental mouse models, providing a platform for testing new therapeutic approaches. By examining molecular signaling pathways, synaptic deficits, and spine dysgenesis in experimental mouse models of autism related disorders we find strong evidence for mTOR to be a critical point of convergence and promising therapeutic target. Copyright © 2015. Published by Elsevier Ireland Ltd.
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