Respiratory phenotypes are distinctly affected in mice with common Rett syndrome mutations MeCP2 T158A and R168X

Bissonnette, John M.; Schaevitz, Laura; Knopp, Sharon J.; Zhou, Zhaolan

doi:10.1016/j.neuroscience.2014.02.043

Cited by 32 publications

(34 citation statements)

References 44 publications

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“…Mouse models of RTT typically report normal respiratory activity under control conditions (inactive, breathing room air) up to PND 20 (63,83) followed shortly thereafter by abnormalities in post-sigh breathing (63), and later hyper- (84,85) or hypo-ventilation (62,83,86,87) with increased tidal volume (86,88) in conjunction with increased apneic frequency and duration (89–91). These respiratory abnormalities are partly recapitulated in juvenile and adult Mecp2 ZFN/y rats, which demonstrate decreased respiratory frequency, as well as Mecp2 ZFN/+ rats, which show increased frequency.…”

Section: Discussionmentioning

confidence: 99%

MeCP2 deficiency results in robust Rett-like behavioural and motor deficits in male and female rats

et al. 2016

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Since the identification of MECP2 as the causative gene in the majority of Rett Syndrome (RTT) cases, transgenic mouse models have played a critical role in our understanding of this disease. The use of additional mammalian RTT models offers the promise of further elucidating critical early mechanisms of disease as well as providing new avenues for translational studies. We have identified significant abnormalities in growth as well as motor and behavioural function in a novel zinc-finger nuclease model of RTT utilizing both male and female rats throughout development. Male rats lacking MeCP2 (Mecp2ZFN/y) were noticeably symptomatic as early as postnatal day 21, with most dying by postnatal day 55, while females lacking one copy of Mecp2 (Mecp2ZFN/+) displayed a more protracted disease course. Brain weights of Mecp2ZFN/y and Mecp2ZFN/+ rats were significantly reduced by postnatal day 14 and 21, respectively. Early motor and breathing abnormalities were apparent in Mecp2ZFN/y rats, whereas Mecp2ZFN/+ rats displayed functional irregularities later in development. The large size of this species will provide profound advantages in the identification of early disease mechanisms and the development of appropriately timed therapeutics. The current study establishes a foundational basis for the continued utilization of this rat model in future RTT research.

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Section: Discussionmentioning

confidence: 99%

MeCP2 deficiency results in robust Rett-like behavioural and motor deficits in male and female rats

et al. 2016

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“…MeCP2 is highly expressed in astrocytes (Yasui et al, 2013) and loss of MeCP2 leads to astroglial dysfunction (Okabe et al, 2012). In a mouse model of Rett syndrome (global MeCP2 gene knockout), sensitivity of brainstem astrocytes to changes in PCO 2 /pH is markedly reduced (Turovsky, Karagiannis, Abdala, & Gourine, 2015) and ventilatory CO 2 sensitivity is severely impaired (Bissonnette, Schaevitz, Knopp, & Zhou, 2014).…”

Section: Sensing Carbon Dioxide and Phmentioning

confidence: 99%

Brain metabolic sensing and metabolic signaling at the level of an astrocyte

Marina

Turovsky

Christie

et al. 2017

Glia

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Astrocytes support neuronal function by providing essential structural and nutritional support, neurotransmitter trafficking and recycling and may also contribute to brain information processing. In this article we review published results and report new data suggesting that astrocytes function as versatile metabolic sensors of central nervous system (CNS) milieu and play an important role in the maintenance of brain metabolic homeostasis. We discuss anatomical and functional features of astrocytes that allow them to detect and respond to changes in the brain parenchymal levels of metabolic substrates (oxygen and glucose), and metabolic waste products (carbon dioxide). We report data suggesting that astrocytes are also sensitive to circulating endocrine signals—hormones like ghrelin, glucagon‐like peptide‐1 and leptin, that have a major impact on the CNS mechanisms controlling food intake and energy balance. We discuss signaling mechanisms that mediate communication between astrocytes and neurons and consider how these mechanisms are recruited by astrocytes activated in response to various metabolic challenges. We review experimental data suggesting that astrocytes modulate the activities of the respiratory and autonomic neuronal networks that ensure adaptive changes in breathing and sympathetic drive in order to support the physiological and behavioral demands of the organism in ever‐changing environmental conditions. Finally, we discuss evidence suggesting that altered astroglial function may contribute to the pathogenesis of disparate neurological, respiratory and cardiovascular disorders such as Rett syndrome and systemic arterial hypertension.

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“…While the generally accepted view holds that response to CO 2 is a property of neurons, recent work has pointed to an important contribution from astrocytes (14,15,18,21,27). Respiratory CO 2 ventilatory response is significantly depressed in mice that lack or are deficient in the X-linked transcription factor methyl-CpG-binding protein 2 (MeCP2) (6,50,58). Mutations in this nuclear protein cause the neurological disorder Rett syndrome (RTT) (3).…”

mentioning

confidence: 99%

Conditional depletion of methyl-CpG-binding protein 2 in astrocytes depresses the hypercapnic ventilatory response in mice

Garg

Lioy

Knopp³

et al. 2015

Journal of Applied Physiology

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Garg SK, Lioy DT, Knopp SJ, Bissonnette JM. Conditional depletion of methyl-CpG-binding protein 2 in astrocytes depresses the hypercapnic ventilatory response in mice. J Appl Physiol 119: 670 -676, 2015. First published July 23, 2015 doi:10.1152/japplphysiol.00411.2015Mice that are deficient in the transcription factor methyl-CpG-binding protein 2 (MeCP2) have a depressed hypercapnic ventilatory response (HCVR). The expression of MeCP2 can be selectively removed from astrocytes or neurons, thus offering a tool to dissect the role of this transcription factor in astrocytes from that in neurons. Studies were carried out in the progeny of mice that were a cross between those harboring a tamoxifen (TAM)-inducible Cre recombinase transgene driven by the human astrocytic glial fibrillary acidic protein (hGFAP) promoter, or Cre recombinase under control of the synapsin promoter, with mice containing a Cre-excisable exon III in the Mecp2 gene. The TAM-conditional excision of the Mecp2 exon allowed the respiratory CO2 response to be studied in the same animals before and after selective depletion of MeCP2 in astrocytes. Immunohistochemistry showed that following TAM treatment only ϳ20% of GFAP-labeled cells in the retrotrapazoid nucleus and in the raphé magnus were positive for MeCP2. The slope of the relative increase in minute ventilation as a function of 1, 3, and 5% inspired CO2 was depressed in mice with depleted astrocyte MeCP2 compared with wild-type littermates. In contrast, selective depletion of MeCP2 in neurons did not significantly affect slope. While neurons which constitute the respiratory network ultimately determine the ventilatory response to CO2, this study demonstrates that loss of MeCP2 in astrocytes alone is sufficient to result in a dramatic attenuation of the HCVR. We propose that the glial contribution to HCVR is under the control of the MeCP2 gene.astrocyte; hypercapnic ventilatory response; Rett syndrome HYDROGEN ION HOMEOSTASIS IS largely dependent on CO 2 /pH regulation of minute ventilation. Thus the cellular and molecular mechanisms that transduce changes in blood and brain parenchymal CO 2 /pH to increase the rate and depth of breathing are important areas of current study (12,17,18,21,26,27,40). While the generally accepted view holds that response to CO 2 is a property of neurons, recent work has pointed to an important contribution from astrocytes (14,15,18,21,27). Respiratory CO 2 ventilatory response is significantly depressed in mice that lack or are deficient in the X-linked transcription factor methyl-CpG-binding protein 2 (MeCP2) (6,50,58). Mutations in this nuclear protein cause the neurological disorder Rett syndrome (RTT) (3).A previous study suggested that activation of chemosensitive neurons of the retrotrapezoid nucleus (RTN) could affect CO 2 levels by both their intrinsic pH sensitivity of as well as by non-cell-autonomous activity of neighboring astrocytes (19). The extent of astrocyte contribution by release of ATP to signal RTN neurons is unsettled. Photoactivation of a...

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Respiratory phenotypes are distinctly affected in mice with common Rett syndrome mutations MeCP2 T158A and R168X

Cited by 32 publications

References 44 publications

MeCP2 deficiency results in robust Rett-like behavioural and motor deficits in male and female rats

MeCP2 deficiency results in robust Rett-like behavioural and motor deficits in male and female rats

Brain metabolic sensing and metabolic signaling at the level of an astrocyte

Conditional depletion of methyl-CpG-binding protein 2 in astrocytes depresses the hypercapnic ventilatory response in mice

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