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


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.

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    • "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:
    Cerebral Cortex 05/2015; DOI:10.1093/cercor/bhv078 · 8.67 Impact Factor
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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.
    Journal of Neurochemistry 06/2014; 131(1). DOI:10.1111/jnc.12803 · 4.28 Impact Factor
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    • "MECP2 deficient mice, which have been developed to recapitulate the core features of RTT, show significantly higher levels of anxiety-like behaviors (Adachi, Autry, Covington III, & Monteggia, 2009; Fyffe et al., 2008; Gemelli et al., 2006; McGill et al., 2006), and provide evidence of pathologically altered stress-response systems. It appears that MeCP2 modulates or otherwise regulates the expression of the corticotrophin-releasing hormone (Crh) gene, which is a part of a well-established pathway underlying anxiety (Fyffe et al., 2008; LeDoux, 2000; McGill et al., 2006). Although there has not been comparable work specific to anxiety among individuals with RTT, parents and other caregivers commonly report anxiety and stress-related issues. "
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    ABSTRACT: Rett syndrome (RTT) is a neurodevelopmental disorder primarily affecting females. It is characterized by apparently normative development of motor and communicative abilities followed by deterioration in these domains. Stereotypic hand movements are one of the core diagnostic criteria for RTT. There is some anecdotal but limited scientific evidence that changes in hand stereotypy may be a sign of increased anxiety or arousal (i.e., a ‘stress response’) in RTT. Understanding stress responsivity is difficult in RTT because almost all individuals are nonverbal or otherwise severely communicatively impaired. This study used direct behavioral observation to quantify and compare the frequency of hand stereotypy and signs of negative affect during presumed periods of high and low stress associated with functional analysis conditions (negative reinforcement [‘escape’] and control [‘free play’], respectively) for 5 females with RTT (mean age = 17.8; range 4–47). Negative affect was more likely to occur during negative reinforcement (‘stress’) conditions for each participant whereas hand stereotypies did not differ across conditions for any of the participants. Although preliminary, the results suggest that hand stereotypy may not be a valid behavioral ‘stress-response’ indicator in females with RTT. Alternatively, the approach we used may have been limited and not sufficient to evoke a stress response. Either way, more work with direct relevance to improving our understanding of hand stereotypy and anxiety in RTT in relation to social context appears warranted.
    Research in developmental disabilities 05/2014; 35(5). DOI:10.1016/j.ridd.2014.01.011 · 4.41 Impact Factor
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