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: 9.81). 12/2009; 106(51):21966-71. DOI: 10.1073/pnas.0912257106
Source: PubMed

ABSTRACT 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, Jul 28, 2015
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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 · 4.24 Impact Factor
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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.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 06/2014; 39(12). DOI:10.1038/npp.2014.136 · 8.68 Impact Factor
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    • "Deficiencies of 5-HT neurotransmission have been found both in humans suffering from Rett syndrome and in mouse models of the disease. In women with known MeCP2 mutations who met the clinical criteria for Rett syndrome, low spinal fluid levels of a 5-HT metabolite were found (Samaco et al., 2009). Low levels of 5-HT were also found in the brain of MeCP2 knockout male mice and were progressive with development (Ide et al., 2005; Viemari et al., 2005). "
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    ABSTRACT: Rett syndrome is a neurological disorder caused by loss of function of methyl-CpG-binding protein 2 (MeCP2). Reduced function of this ubiquitous transcriptional regulator has a devastating effect on the central nervous system. One of the most severe and life-threatening presentations of this syndrome is brainstem dysfunction, which results in autonomic disturbances such as breathing deficits, typified by episodes of breathing cessation intercalated with episodes of hyperventilation or irregular breathing. Defects in numerous neurotransmitter systems have been observed in Rett syndrome both in animal models and patients. Here we dedicate special attention to serotonin due to its role in promoting regular breathing, increasing vagal tone, regulating mood, alleviating Parkinsonian-like symptoms and potential for therapeutic translation. A promising new symptomatic strategy currently focuses on regulation of serotonergic function using highly selective serotonin type 1A (5-HT1A) “biased agonists”. We address this newly emerging therapy for respiratory brainstem dysfunction and challenges for translation with a holistic perspective of Rett syndrome, considering potential mood and motor effects.
    Frontiers in Physiology 05/2014; 5. DOI:10.3389/fphys.2014.00205 · 3.50 Impact Factor
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