Reversibility of functional deficits in experimental models of Rett syndrome

Cobb, Stuart; Guy, Jacky; Bird, Adrian

doi:10.1042/bst0380498

Cited by 62 publications

(47 citation statements)

References 84 publications

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“…2, 4, 7), there was probably a greater accumulation of neuronal MeCP2 from P14 to P30 in the MeCP2 shRNA group than in the control group. Therefore, the dramatic increase of MAP-2 as well as the reduction of DCX and Tuj1 at P30 may have resulted from the potential overexpression of neuronal MeCP2 in this period, as previously reported [43][44][45][46][47]. Last but not least, we found that Purkinje cells were more lightly stained by CB in the MeCP2 shRNA group at P30.…”

Section: Function Of Mecp2 In the Postnatal Rat Cerebellumsupporting

confidence: 71%

Expression of Phospho-MeCP2s in the Developing Rat Brain and Function of Postnatal MeCP2 in Cerebellar Neural Cell Development

Liu

Sun

2016

Neurosci. Bull.

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Abnormal expression and dysfunction of methyl-CpG binding protein 2 (MeCP2) cause Rett syndrome (RTT). The diverse phosphorylation modifications modulate MeCP2 function in neural cells. Using western blot and immunohistochemistry, we examined the expression patterns of MeCP2 and three phospho-MeCP2s (pMeCP2s) in the developing rat brain. The expression of MeCP2 and phospho-S80 (pS80) MeCP2 increased while pS421 MeCP2 and pS292 MeCP2 decreased with brain maturation. In contrast to the nuclear localization of MeCP2 and pS80 MeCP2, pS421 MeCP2 and pS292 MeCP2 were mainly expressed in the cytoplasmic compartment. Apart from their distribution in neurons, they were also detected at a low level in astrocytes. Postnatallyinitiated MeCP2 deficiency affected cerebellar neural cell development, as determined by the abnormal expression of GFAP, DCX, Tuj1, MAP-2, and calbindin-D28k. Together, these results demonstrate that MeCP2 and diverse pMeCP2s have distinct features of spatio-temporal expression in the rat brain, and that the precise levels of MeCP2 in the postnatal period are vital to cerebellar neural cell development.

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Section: Function Of Mecp2 In the Postnatal Rat Cerebellumsupporting

confidence: 71%

Expression of Phospho-MeCP2s in the Developing Rat Brain and Function of Postnatal MeCP2 in Cerebellar Neural Cell Development

Liu

Sun

2016

Neurosci. Bull.

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“…The conventional view that loss of MeCP2 during a critical developmental window causes irreversible changes in brain structure and cellular function has been significantly modified with a striking reversal of phenotype when Mecp2 expression is reactivated in an inducible transgenic mouse model Cobb et al, 2010;Guy et al, 2011;Lioy et al, 2011). Patients with RTT appear normal at birth but progressively suffer from a number of behavioral disorders, including severe breathing irregularities that can be highly variable, both among affected individuals and within individuals, depending, for example, on the level of behavioral arousal.…”

Section: Introductionmentioning

confidence: 99%

Anxiety-Related Mechanisms of Respiratory Dysfunction in a Mouse Model of Rett Syndrome

et al. 2012

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Rett syndrome (RTT) is a severe neurological disorder that is associated with mutations in the methyl-CpG binding protein 2 (MECP2) gene. RTT patients suffer from mental retardation and behavioral disorders, including heightened anxiety and state-dependent breathing irregularities, such as hyperventilation and apnea. Many symptoms are recapitulated by the Mecp2-null male mice (Mecp2 Ϫ/y ). To characterize developmental progression of the respiratory phenotype and explore underlying mechanisms, we examined Mecp2 Ϫ/y and wild-type (WT) mice from presymptomatic periods to end-stage disease. We monitored breathing patterns of unrestrained mice during wake-sleep states and while altering stress levels using movement restraint or threatening odorant (trimethylthiazoline). Respiratory motor patterns generated by in situ working heart-brainstem preparations (WHBPs) were measured to assess function of brainstem respiratory networks isolated from suprapontine structures. Data revealed two general stages of respiratory dysfunction in Mecp2 Ϫ/y mice. At the early stage, respiratory abnormalities were limited to wakefulness, correlated with markers of stress (increased fecal deposition and blood corticosterone levels), and alleviated by antalarmin (corticotropin releasing hormone receptor 1 antagonist). Furthermore, the respiratory rhythm generated by WHBPs was similar in WT and Mecp2 Ϫ/y mice. During the later stage, respiratory abnormalities were evident during wakefulness and sleep. Also, WHBPs from Mecp2 Ϫ/y showed central apneas. We conclude that, at early disease stages, stress-related modulation from suprapontine structures is a significant factor in the Mecp2 Ϫ/y respiratory phenotype and that anxiolytics may be effective. At later stages, abnormalities of brainstem respiratory networks are a significant cause of irregular breathing patterns and central apneas.

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“…The encoded protein, methyl CpG binding protein 2, regulates expression of multiple genes, including BDNF, encoding brain-derived neurotrophic factor. Returning Mecp2 gene function in adulthood rescues synaptic function as well as motor decline and premature death observed in the mouse model of Rett syndrome, suggesting that treatment may be possible even after the period of initial regression (Cobb et al, 2010).…”

Section: Rare Simple Genetic Phenocopies Could Reveal New Treatment mentioning

confidence: 96%

Intervention in the Context of Development: Pathways Toward New Treatments

Veenstra‐VanderWeele

Warren

2014

Neuropsychopharmacol

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Neuropsychiatric disorders vary substantially in age of onset but are best understood within the context of neurodevelopment. Here, we review opportunities for intervention at critical points in developmental trajectories. We begin by discussing potential opportunities to prevent neuropsychiatric disorders. Once symptoms begin to emerge, a number of interventions have been studied either before a diagnosis can be made or shortly after diagnosis. Although some of these interventions are helpful, few are based upon an understanding of pathophysiology, and most ameliorate rather than resolve symptoms. As such, in the next portion of the review, we turn our discussion to genetic syndromes that are rare phenocopies of common diagnoses such as autism spectrum disorder or schizophrenia. Cellular or animal models of these syndromes point to specific regulatory or signaling pathways. As examples, findings from the mouse models of Fragile X and Rett syndromes point to potential treatments now being tested in randomized clinical trials. Paralleling oncology, we can hope that our treatments will move from nonspecific, like chemotherapies thrown at a wide range of tumor types, to specific, like the protein kinase inhibitors that target molecularly defined tumors. Some of these targeted treatments later show benefit for a broader, yet specific, array of cancers. We can hope that medications developed within rare neurodevelopmental syndromes will similarly help subgroups of patients with disruptions in overlapping signaling pathways. The insights gleaned from treatment development in rare phenocopy syndromes may also teach us how to test treatments based upon emerging common genetic or environmental risk factors.

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Reversibility of functional deficits in experimental models of Rett syndrome

Cited by 62 publications

References 84 publications

Expression of Phospho-MeCP2s in the Developing Rat Brain and Function of Postnatal MeCP2 in Cerebellar Neural Cell Development

Expression of Phospho-MeCP2s in the Developing Rat Brain and Function of Postnatal MeCP2 in Cerebellar Neural Cell Development

Anxiety-Related Mechanisms of Respiratory Dysfunction in a Mouse Model of Rett Syndrome

Intervention in the Context of Development: Pathways Toward New Treatments

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