Article

The Disease Progression of Mecp2 Mutant Mice Is Affected by the Level of BDNF Expression

Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA.
Neuron (Impact Factor: 15.05). 03/2006; 49(3):341-8. DOI: 10.1016/j.neuron.2005.12.027
Source: PubMed

ABSTRACT

Mutations in the MECP2 gene cause Rett syndrome (RTT). Bdnf is a MeCP2 target gene; however, its role in RTT pathogenesis is unknown. We examined Bdnf conditional mutant mice for RTT-relevant pathologies and observed that loss of BDNF caused smaller brain size, smaller CA2 neurons, smaller glomerulus size, and a characteristic hindlimb-clasping phenotype. BDNF protein level was reduced in Mecp2 mutant mice, and deletion of Bdnf in Mecp2 mutants caused an earlier onset of RTT-like symptoms. To assess whether this interaction was functional and potentially therapeutically relevant, we increased BDNF expression in the Mecp2 mutant brain with a conditional Bdnf transgene. BDNF overexpression extended the lifespan, rescued a locomotor defect, and reversed an electrophysiological deficit observed in Mecp2 mutants. Our results provide in vivo evidence for a functional interaction between Mecp2 and Bdnf and demonstrate the physiological significance of altered BDNF expression/signaling in RTT disease progression.

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    • "However, it is currently unclear whether MeCP2 activates or represses transcription of the Bdnf gene. In vivo studies have reported decreased BDNF protein in Mecp2-deficient mutants (Chang et al., 2006; Wang et al., 2006; Kondo et al., 2008), prompting Fyffe et al. (2008) to propose that MeCP2 is an activator of Bdnf transcription. Our results quantifying Bdnf expression in WT and Het littermates suggest that MeCP2 may regulate Bdnf transcription differently in different brain regions. "
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    ABSTRACT: Rett syndrome is a neurodevelopmental disorder associated with mutations in the X-linked gene encoding methyl-CpG-binding protein 2 (MeCP2) and consequent dysregulation of brain maturation. Patients suffer from a range of debilitating physical symptoms, however behavioural and emotional symptoms also severely affect their quality of life. Here we present previously unreported and clinically relevant affective dysfunction in the female heterozygous Mecp2(tm1Tam) mouse model of Rett syndrome (129sv and C57BL6 mixed background). The affective dysfunction and aberrant anxiety-related behaviour of the Mecp2(+/-) mice were found to be reversible with environmental enrichment from 4 weeks of age. The effect of exercise alone (via wheel running) was also explored, providing the first evidence that increased voluntary physical activity in an animal model of Rett syndrome is beneficial for some phenotypes. Mecp2(+/-) mutants displayed elevated corticosterone despite decreased Crh expression, demonstrating HPA-axis dysregulation. Environmental enrichment of Mecp2(+/-) mice normalised basal serum corticosterone and hippocampal BDNF protein levels. The enrichment-induced rescue appears independent of the transcriptional regulation of the MeCP2 targets Bdnf exon 4 and Crh. These findings provide new insight into the neurodevelopmental role of MeCP2 and pathogenesis of Rett syndrome, in particular the affective dysfunction. The positive outcomes of environmental stimulation and physical exercise have implications for the development of therapies targeting the affective symptoms, as well as behavioural and cognitive dimensions, of this devastating neurodevelopmental disorder. This article is protected by copyright. All rights reserved. © 2015 Wiley Periodicals, Inc.
    No preview · Article · May 2015 · Developmental Neurobiology
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    • "MeCP2 is an important regulator of BDNF transcription (Chen et al., 2003; Martinowich et al., 2003). BDNF protein levels are reduced in conditions of MeCP2 deficiency (Chang et al., 2006; Wang et al., 2006), while stimulation of BDNF receptors improves respiratory pattern in MePC2 null mice (Schmid et al., 2012; Kron et al., 2014). Part of BDNF signalling pathway involves activation of certain transient receptor potential channels (TRPC) (Amaral et al., 2007). "
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    ABSTRACT: Rett syndrome, a prototypical neurological disorder caused by loss of function of the transcriptional regulator methyl-CpG-binding protein 2 (MeCP2) gene, is associated with severely disordered breathing pattern and reduced ventilatory CO2 sensitivity. In a mouse model of Rett syndrome (MeCP2 knockout), re-introduction of the MeCP2 gene selectively in astrocytes rescues normal respiratory phenotype. In the present study we determined whether metabolic and/or signalling function of astrocytes is affected by testing the hypothesis that in conditions of MeCP2 deficiency medullary astrocytes are unable to produce/release appropriate amounts of lactate or detect changes in PCO2 /[H(+) ], or both. No differences in tonic or hypoxia-induced release of lactate from the ventral surface of the medulla oblongata or cerebral cortex in brain slices of MeCP2-knockout and wild-type mice were found. In brainstem slices of wild-type mice, respiratory acidosis triggered robust elevations in [Ca(2+) ]i in astrocytes residing near the ventral surface of the medulla oblongata. The magnitude of CO2 -induced [Ca(2+) ]i responses in medullary astrocytes was markedly reduced in conditions of MeCP2 deficiency, whereas [Ca(2+) ]i responses to ATP were unaffected. These data suggest that (i) metabolic function of astrocytes in releasing lactate into the extracellular space is not affected by MeCP2 deficiency; (ii) MeCP2 deficiency impairs the ability of medullary astrocytes to sense changes in PCO2 /[H(+) ]. Taken together with the evidence of severely blunted ventilatory sensitivity to CO2 in mice with conditional MeCP2 deletion in astroglia, these data support the hypothesis of an important role played by astrocytes in central respiratory CO2 /pH chemosensitivity. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Full-text · Article · May 2015 · The Journal of Physiology
    • "For example , if the gene and protein expression of BDNF was solely repressed by MeCP2, one would expect to see and overexpression of BDNF in RTT due to the loss of MeCP2. However , studies involving MeCP2 null mice [61, 175, 176] as well as human RTT post-mortem brain samples [178] show decreased levels of BDNF gene and protein expression demonstrating that there are other repressors other than MeCP2 that regulate BDNF expression. In fact, RE1 silencing transcription factor (REST) and CoREST are two transcriptional repressors that are involved in transcriptional repression of BDNF gene [182] . "
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    ABSTRACT: Multiple sclerosis (MS) is a chronic progressive, neurological disease characterized by the targeted immune system-mediated destruction of central nervous system (CNS) myelin. Autoreactive CD4+ T helper cells have a key role in orchestrating MS-induced myelin damage. Once activated, circulating Th1-cells secrete a variety of inflammatory cytokines that foster the breakdown of blood-brain barrier (BBB) eventually infiltrating into the CNS. Inside the CNS, they become reactivated upon exposure to the myelin structural proteins and continue to produce inflammatory cytokines such as tumor necrosis factor α (TNFα) that leads to direct activation of antibodies and macrophages that are involved in the phagocytosis of myelin. Proliferating oligodendrocyte precursors (OPs) migrating to the lesion sites are capable of acute remyelination but unable to completely repair or restore the immune system-mediated myelin damage. This results in various permanent clinical neurological disabilities such as cognitive dysfunction, fatigue, bowel/bladder abnormalities, and neuropathic pain. At present, there is no cure for MS. Recent remyelination and/or myelin repair strategies have focused on the role of the neurotrophin brain-derived neurotrophic factor (BDNF) and its upstream transcriptional repressor methyl CpG binding protein (MeCP2). Research in the field of epigenetic therapeutics involving histone deacetylase (HDAC) inhibitors and lysine acetyl transferase (KAT) inhibitors is being explored to repress the detrimental effects of MeCP2. This review will address the role of MeCP2 and BDNF in remyelination and/or myelin repair and the potential of HDAC and KAT inhibitors as novel therapeutic interventions for MS.
    No preview · Article · Jan 2015 · Molecular Neurobiology
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