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.

Download full-text


Available from: Christian Rosenmund, Jan 13, 2014
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    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.
    Neuroscience Letters 01/2015; DOI:10.1016/j.neulet.2015.01.011 · 2.06 Impact Factor
  • Source
    • "Neurological phenotypes involve an imbalance of excitation and inhibition in neural circuits caused by too little or too much MeCP2 activity. Using a reduced experimental system consisting in growing single neurons on micro-island cultures, he provided evidence for specific determination of cell intrinsic mechanisms of MeCP2 regulation (Chao et al., 2007, 2010). "
    [Show abstract] [Hide abstract]
    ABSTRACT: New progresses into the molecular and cellular mechanisms of autism spectrum disorders (ASDs) have been discussed in 1 day international symposium held in Pavia (Italy) on July 4th, 2014 entitled "synapses as therapeutic targets for autism spectrum disorders" (satellite of the FENS Forum for Neuroscience, Milan, 2014). In particular, world experts in the field have highlighted how animal models of ASDs have greatly advanced our understanding of the molecular pathways involved in synaptic dysfunction leading sometimes to "synaptic clinical trials" in children.
    Frontiers in Cellular Neuroscience 09/2014; 8:309. DOI:10.3389/fncel.2014.00309 · 4.18 Impact Factor
Show more