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


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.
    Developmental Neurobiology 05/2015; DOI:10.1002/dneu.22308 · 3.37 Impact Factor
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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.
    The Journal of Physiology 05/2015; 593(14). DOI:10.1113/JP270369 · 5.04 Impact Factor
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    • "been elucidated following studies on Mecp2 null mice , used as model for Rett Syndrome ( RTT ) . MeCP2 codes for methyl - CpG - binding protein - 2 , the gene , that is mutated in RTT ( Amir et al . , 1999 ) . This work on Mecp2 null mice has pointed out BDNF deficits as the possible cause of the neurological dysfunction observed in RTT patients ( Chang et al . , 2006 ; Wang et al . , 2006 ; Ogier et al . , 2007 ; Kline et al . , 2010 ) . BDNF is a transcriptional target of MeCP2 ( Katz , 2014 ) and the main areas of BDNF loss in Mecp2 mutants correspond to the NG and the NTS ; the latter is the main target of peripheral sensory neurons that convey visceral afferent input to the central autonomic nuc"
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    ABSTRACT: Brain-derived neurotrophic factor, BDNF, is one of the most important neurotrophic factors acting in the peripheral and central nervous system. In the auditory system its function was initially defined by using constitutive knockout mouse mutants and shown to be essential for survival of neurons and afferent innervation of hair cells in the peripheral auditory system. Further examination of BDNF null mutants also revealed a more complex requirement during re-innervation processes involving the efferent system of the cochlea. Using adult mouse mutants defective in BDNF signaling, it could be shown that a tonotopical gradient of BDNF expression within cochlear neurons is required for maintenance of a specific spatial innervation pattern of outer hair cells and inner hair cells. Additionally, BDNF is required for maintenance of voltage-gated potassium channels (KV) in cochlear neurons, which may form part of a maturation step within the ascending auditory pathway with onset of hearing and might be essential for cortical acuity of sound-processing and experience-dependent plasticity. A presumptive harmful role of BDNF during acoustic trauma and consequences of a loss of cochlear BDNF during aging are discussed in the context of a partial reversion of this maturation step. We compare the potentially beneficial and harmful roles of BDNF for the mature auditory system with those BDNF functions known in other sensory circuits, such as the vestibular, visual, olfactory, or somatosensory system.
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