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Deletion of Mecp2 in Sim1-Expressing Neurons Reveals a Critical Role for MeCP2 in Feeding Behavior, Aggression, and the Response to Stress

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Neuron (Impact Factor: 15.05). 10/2008; 59(6):947-58. DOI: 10.1016/j.neuron.2008.07.030
Source: PubMed

ABSTRACT

Rett Syndrome (RTT) is an autism spectrum disorder caused by mutations in the X-linked gene encoding methyl-CpG binding protein 2 (MeCP2). In order to map the neuroanatomic origins of the complex neuropsychiatric behaviors observed in patients with RTT and to uncover endogenous functions of MeCP2 in the hypothalamus, we removed Mecp2 from Sim1-expressing neurons in the hypothalamus using Cre-loxP technology. Loss of MeCP2 in Sim1-expressing neurons resulted in mice that recapitulated the abnormal physiological stress response that is seen upon MeCP2 dysfunction in the entire brain. Surprisingly, we also uncovered a role for MeCP2 in the regulation of social and feeding behaviors since the Mecp2 conditional knockout (CKO) mice were aggressive, hyperphagic, and obese. This study demonstrates that deleting Mecp2 in a defined brain region is an excellent approach to map the neuronal origins of complex behaviors and provides new insight about the function of MeCP2 in specific neurons.

    • "Accordingly, many studies have shown that Mecp2 null hippocampal slices are characterized by significant deficits in synaptic transmission (Asaka et al. 2006; Zhang et al. 2008), as well as in synaptic plasticity (Della Sala and Pizzorusso 2014). Interestingly, ablation of Mecp2 in adulthood results in defects of neuronal functions resembling those displayed by animals constitutively missing Mecp2 (Gemelli et al. 2006; Fyffe et al. 2008; McGraw et al. 2011; Cheval et al. 2012; Nguyen et al. 2012). Altogether, these conditional animal models indicate that MeCP2 must play a role in the maintenance of brain functionality at post-natal ages. "
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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: journals.permissions@oup.com.
    No preview · Article · May 2015 · Cerebral Cortex
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    • "However, RTT is an extremely complex and diversified pathology that likely involves several CNS regions and different cell types giving rise to a wide panel of neuropsychiatric features. Over the last few years, several laboratories have demonstrated that different symptoms of RTT may manifest through specific loss of Mecp2 in selected brain regions or neuronal populations (Chen et al. 2001; Fyffe et al. 2008; Samaco et al. 2009; Chao et al. 2010; Lioy et al. 2011; Zhao et al. 2013). While it is thought that loss of Mecp2 produces an excitatory–inhibitory imbalance that may differ between brain areas (see for review Boggio et al. 2010; Shepherd and Katz 2011; Della Sala and Received April 9, 2014; revised manuscript received June 17, 2014; accepted June 24, 2014. "
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    ABSTRACT: Rett syndrome (RTT; MIM312750), a neurodevelopmental disorder predominantly occurring in females, is caused in the majority of cases by sporadic mutations in the gene encoding the transcriptional modulator Methyl-CpG-Binding Protein 2 (MECP2). In mice, impaired MeCP2 function results in severe motor, cognitive, and emotional defects. However, the impact of Mecp2 function on the development and organization of the cortical inhibitory system is still largely unknown. First, we found that MeCP2 expression varies among the major γ-aminobutyric acid-(GABA)-releasing cortical interneurons (INs) subclasses and its nuclear localization differs between neuronal types. The density of calretinin(+) and parvalbumin(+) INs increases in Mecp2 knockout mice (Mecp2(-/y) ) already at early postnatal developmental stages. In contrast, the density of somatostatin(+) INs is not affected. We also found that the development of multipolar-calretinin(+) interneurons is selectively affected by the absence of Mecp2. Additionally, we show that in Mecp2 heterozygous female mice, a model closely mimicking human RTT condition, INs abnormalities are similar to those observed in Mecp2(-/y) mice. Together, our study indicates that loss of function of Mecp2 strongly interferes with the correct establishment of the neocortical inhibitory system producing effects that are specific to different IN subtypes. This article is protected by copyright. All rights reserved.
    Full-text · Article · Jun 2014 · Journal of Neurochemistry
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    • "Their regulation differed depending the brain structures considered, the nature of the reinforcer and operant conditioning-related memory processes. As the mesostriatal dopamine system is activated by food and by drugs of abuse, the data provide new insights into the mechanism by which two proteins involved in cocaine reward (Zachariou et al., 2002;Romieu et al., 2008;Feng and Nestler, 2010), or in food consumption (Fyffe et al., 2008;Danielli et al., 2010;Cui et al., 2012) are differentially regulated. Food restriction induced significant changes in the baseline gene expression of Mecp2, PP1Cβ, HDAC2 and GAD67 in the CPu (Fig. 8b), indicating that the comparison between rats exposed to cocaine administration vs. food delivery in this brain structure has to be taken with caution, notably in respect to the regulation of PP1Cβ by Mecp2. "
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    ABSTRACT: Cocaine exposure induces changes in the expression of numerous genes, in part through epigenetic modifications. We have initially shown that cocaine increases the expression of the chromatin remodeling protein methyl-CpG binding protein 2 (MeCP2) and characterized the protein phosphatase-1Cβ (PP1Cβ) gene, as repressed by passive i.p. cocaine injections through a Mecp2-mediated mechanism involving de novo DNA methylation. Both proteins being involved in learning and memory processes, we investigated whether voluntary cocaine administration would similarly affect their expression using an operant self-administration paradigm. Passive and voluntary i.v. cocaine intake was found to induce Mecp2 and to repress PP1Cβ in the prefrontal cortex and the caudate putamen. This observation is consistent with the role of Mecp2 acting as a transcriptional repressor of PP1Cβ and shows that passive intake was sufficient to alter their expression. Surprisingly, striking differences were observed under the same conditions in food-restricted rats tested for food pellet delivery. In the prefrontal cortex and throughout the striatum, both proteins were induced by food operant conditioning, but remained unaffected by passive food delivery. Although cocaine and food activate a common reward circuit, changes observed in the expression of other genes such as reelin and GAD67 provide new insights into molecular mechanisms differentiating neuroadaptations triggered by each reinforcer. The identification of hitherto unknown genes differentially regulated by drugs of abuse and a natural reinforcer should improve our understanding of how two rewarding stimuli differ in their ability to drive behavior.
    Preview · Article · Jun 2014 · The International Journal of Neuropsychopharmacology
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