Neurobiology of Rett syndrome: a genetic disorder of synapse development

Johnston, Michael V.; Jeon, Ok Hee; Pevsner, Jonathan; Blue, Mary E.; Naidu, Sakku Bai

doi:10.1016/s0387-7604(01)00351-5

Cited by 112 publications

(74 citation statements)

References 43 publications

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“…An important feature of RTT suggested by mouse models therefore is that it is reversible-the CNS circuits involved apparently do not atrophy but rather remain in a labile, immature state (11), inducing maturation subsequently can repair the syndrome's consequences. Clinical observations have suggested RTT as a genetic disorder of synapse development (12), a feature consistent with findings that cortical and hippocampal brain circuits in MeCP2 mutant mice are characterized by reduced excitatory synaptic drive and synapse number (13,14).…”

supporting

confidence: 77%

“…IGF-1 signaling thus offers an attractive target for engaging key molecular pathways to potentially stimulate synaptic maturation and reverse the RTT phenotype, in a format that is more amenable to therapeutic administration to RTT patients. We therefore investigated the potential of (1-3)IGF-1, delivered systemically, to overcome the synaptic and neuronal immaturities that are characteristic of RTT physiopathology (12,32) and ameliorate RTT-like symptoms in a mouse model of the disorder.…”

mentioning

confidence: 99%

“…We then asked whether MeCP2 mutant mice exhibited deficits in neurons and synapses of the brain consistent with a framework of altered synaptic maturation (12) and whether these changes could be impacted by treatment with (1-3)IGF-1. Since neurological correlates of physiological deficits are likely to be restricted to specific brain regions rather than the whole brain (3,36), we focused our analysis on motor cortex in correspondence with the described motor phenotypes in MeCP2 mutant mice.…”

mentioning

confidence: 99%

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Partial reversal of Rett Syndrome-like symptoms in MeCP2 mutant mice

Tropea

Giacometti

Wilson

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

511

442

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supporting

confidence: 77%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Partial reversal of Rett Syndrome-like symptoms in MeCP2 mutant mice

Tropea

Giacometti

Wilson

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

511

442

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“…Like Fragile X syndrome, Rett syndrome (RTT) is an X-linked developmental disorder of cognition and behavior that has a major impact on the development and plasticity of synapses (43). Most males with RTT do not survive, but girls develop characteristic stereotyped handwringing movements, severe cognitive impairment, acquired microcephaly, seizures, and disorders of breathing and autonomic dysfunction after a period of relative normality in the first year of life.…”

Section: Synaptic Abnormalities In Rett Syndromementioning

confidence: 99%

Plasticity and injury in the developing brain

Johnston¹,

Ishida²,

Ishida³

et al. 2009

Brain and Development

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190

125

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The child's brain is more malleable or plastic than that of adults and this accounts for the ability of children to learn new skills quickly or recovery from brain injuries. Several mechanisms contribute to this ability including overproduction and deletion of neurons and synapses, and activity-dependent stabilization of synapses. The molecular mechanisms for activity dependent synaptic plasticity are being discovered and this is leading to a better understanding of the pathogenesis of several disorders including neurofibromatosis, tuberous sclerosis, Fragile X syndrome and Rett syndrome. Many of the same pathways involved in synaptic plasticity, such as glutamate-mediated excitation, can also mediate brain injury when the brain is exposed to stress or energy failure such as hypoxia-ischemia. Recent evidence indicates that cell death pathways activated by injury differ between males and females. This new information about the molecular pathways involved in brain plasticity and injury are leading to insights that will provide better therapies for pediatric neurological disorders. KeywordsPlasticity; Injury; Fragile X Syndrome; Rett Syndrome; Hypoxia-Ischemia; NMDA; AMPA; Periventricular Leukomalacia Many disorders and injuries of the developing brain affect the basic mechanisms that allow the nervous system to be shaped by experience during childhood. These mechanisms provide the substrate for brain plasticity (kasosei in Japanese), which is much more active in children than in adults. Plasticity in the child's brain is enhanced because the organization of networks of *Correspondence: 707 North Broadway, Baltimore, MD 21205, Fax: 443-923-9317 Phone: 443-923-9315, Johnston@kennedykrieger.org. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. neuronal synapses as well as white matter pathways remain "under construction" well into adolescence and even later(1). Accordingly, the effects of intensive learning in school, exposure to a second language or practice in athletics has a much greater impact on children than adults. Several neurobiological mechanism contribute to brain plasticity, including an over-production of neurons in early development, apoptosis or programmed cell death of excessive neurons, overproduction and elimination of immature synapses in childhood, and continuous stabilization and strengthening of synaptic connections later in life(2). In this review we focus on some mechanisms for synaptic plasticity, and emerging evidence that these processes are disrupted in several pediatric neurological disorders. NIH Public Access Synaptic PlasticitySynaptic p...

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“…5 For example, in Rett syndrome, gene expression patterns in the frontal cortex and the basal ganglia have been shown to change with age. 6 As such, it is important to look not only at the interactions between genotype and behavior in adults, but also in children at different stages of development. Recently, Diamond et al 7 described the effect of a polymorphism in a gene related to dopamine metabolism on cognitive function in developing children (aged 6.8-14.6 years) and reported that different alleles differentially affected cognitive functioning, even though these functions were thought to rely on similar areas of prefrontal cortex.…”

mentioning

confidence: 99%

Differential effects of DRD4 and DAT1 genotype on fronto-striatal gray matter volumes in a sample of subjects with attention deficit hyperactivity disorder, their unaffected siblings, and controls

et al. 2005

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Genetic influences on behavior are complex and, as such, the effect of any single gene is likely to be modest. Neuroimaging measures may serve as a biological intermediate phenotype to investigate the effect of genes on human behavior. In particular, it is possible to constrain investigations by prior knowledge of gene characteristics and by including samples of subjects where the distribution of phenotypic variance is both wide and under heritable influences. Here, we use this approach to show a dissociation between the effects of two dopamine genes that are differentially expressed in the brain. We show that the DAT1 gene, a gene expressed predominantly in the basal ganglia, preferentially influences caudate volume, whereas the DRD4 gene, a gene expressed predominantly in the prefrontal cortex, preferentially influences prefrontal gray matter volume in a sample of subjects including subjects with ADHD, their unaffected siblings, and healthy controls. This demonstrates that, by constraining our investigations by prior knowledge of gene expression, including samples in which the distribution of phenotypic variance is wide and under heritable influences, and by using intermediate phenotypes, such as neuroimaging, we may begin to map out the pathways by which genes influence behavior. Investigators interested in the effect of genes on behavior face a challenge in that behavior is complex, and is likely affected by multiple genes, as well as gene-gene and gene-environment interactions. As such, the effect of any single gene on behavior is probably only small. Indeed, studies investigating the effect of genotype on behavior have reported modest associations. For example, Fossella et al 1 described the influence of four genes related to dopamine function on measures of executive attention and report small effect sizes. Furthermore, their effects were subtle in that not all aspects of executive attention were affected and that genes had differential effects. 1

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Neurobiology of Rett syndrome: a genetic disorder of synapse development

Cited by 112 publications

References 43 publications

Partial reversal of Rett Syndrome-like symptoms in MeCP2 mutant mice

Partial reversal of Rett Syndrome-like symptoms in MeCP2 mutant mice

Plasticity and injury in the developing brain

Differential effects of DRD4 and DAT1 genotype on fronto-striatal gray matter volumes in a sample of subjects with attention deficit hyperactivity disorder, their unaffected siblings, and controls

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