Loss of MECP2 in aminergic neurons causes cell-autonomous defects in neurotransmitter synthesis and specific behavioral abnormalities

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 12/2009; 106(51):21966-71. DOI: 10.1073/pnas.0912257106
Source: PubMed


Rett syndrome (RTT) is characterized by specific motor, cognitive, and behavioral deficits. Because several of these abnormalities occur in other disease states associated with alterations in aminergic neurotransmitters, we investigated the contribution of such alterations to RTT pathogenesis. We found that both individuals with RTT and Mecp2-null mice have lower-than-normal levels of aminergic metabolites and content. Deleting Mecp2 from either TH-positive dopaminergic and noradrenergic neurons or PET1-positive serotonergic neurons in mice decreased corresponding neurotransmitter concentration and specific phenotypes, likely through MeCP2 regulation of rate-limiting enzymes involved in aminergic neurotransmitter production. These data support a cell-autonomous, MeCP2-dependent mechanism for the regulation of aminergic neurotransmitter synthesis contributing to unique behavioral phenotypes.

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Available from: Hsiao-Tuan Chao
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    • "Therefore, we predicted that Mecp2 mutant mice would be less anxious and fearful in a battery of emotion-relevant behavioral tasks as evidenced by reductions in flight, freezing and defensive behaviors. Methyl CpG binding protein 2 (Mecp2) is a DNA binding protein intricately involved in the transcription of a variety of genes [9] [10] [11] [12] [13] [14]. Mecp2 recognizes methylated DNA in gene promoter regions and recruits transcriptional modulators such as histone deacetylases that alter chromatin packaging [15]. "
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    ABSTRACT: Rett syndrome is a Pervasive Developmental Disorder (PDD) associated with de novo mutations of the methyl CpG-binding protein 2 (MECP2) gene. Mecp2 functions as a transcription factor that regulating the expression of hundreds of genes. Identification of the role of Mecp2 in specific neurodevelopmental symptoms remains an important research aim. We previously demonstrated that male mice possessing a truncation mutation in Mecp2 are hyper-social. We predicted that reduced fear or anxiety might underlie this enhanced affiliation. In order to probe risk assessment and anxiety-like behavior, we compared Mecp2 truncation mutants to their wild-type littermates in the elevated plus maze and elevated zero maze. Additionally, subjects were administered the mouse defense test battery to evaluate unconditioned fear- and panic-like behavior to a graded set of threat scenarios and a predator stimulus. Mutant mice showed no significant changes in anxiety-like behavior. Yet, they displayed hyper-reactive escape and defensive behaviors to an animate predatory threat stimulus. Notably, mutant mice engaged in exaggerated active defense responding to threat stimuli at nearly all phases of the fear battery. These results reveal abnormalities in emotion regulation in Mecp2 mutants particularly in response to ecologically relevant threats. This hyper-responsivity suggests that transcriptional targets of Mecp2 are critical to emotion regulation. Moreover, we suggest that detailed analysis of defensive behavior and aggression with ethologically relevant tasks provides an avenue to interrogate gene-behavior mechanisms neurodevelopmental and other psychiatric conditions. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Mar 2015 · Physiology & Behavior
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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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    • "As previously described not only in RTT patients, but also in RTT model mice, the levels of norepinephrine and dopamine are reduced (Ide et al., 2005) and Th-expressing neurons are deficient (Viemari et al., 2005). A deficiency in the midbrain (MB) of catecholaminergic metabolism in Mecp2 KO mice has also been described (Samaco et al., 2009). The midbrain dopaminergic (mDA) area substantia nigra pars compacta (SNpc) regulates the production of motor strategies (Blandini et al., 2000) and dopaminergic deficit is also the cause of motor deficits in Parkinson disease (Jenner et al., 2008). "
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    ABSTRACT: Rett Syndrome is a neurodevelopmental autism spectrum disorder caused by mutations in the gene coding for methyl CpG-binding protein (MeCP2). The disease is characterized by abnormal motor, respiratory, cognitive impairment, and autistic-like behaviors. No effective treatment of the disorder is available. Mecp2 knockout mice have a range of physiological and neurological abnormalities that resemble the human syndrome and can be used as a model to interrogate new therapies. Herein, we show that the combined administration of Levodopa and a Dopa decarboxylase inhibitor in Rett syndrome mouse models is well tolerated, diminishes Rett syndrome-associated symptoms and increases lifespan. The amelioration of Rett syndrome symptomatology is particularly significant in those features controlled by the dopaminergic pathway in the nigrostratium, such as mobility, tremor and breathing. Most important, the improvement of the Rett syndrome phenotype upon use of the combined treatment is reflected at the cellular level by the development of neuronal dendritic growth. However, much work is required to extend the duration of the benefit of the described preclinical treatment.Neuropsychopharmacology accepted article preview online, 11 June 2014; doi:10.1038/npp.2014.136.
    Full-text · Article · Jun 2014 · Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology
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