Reversing Neurodevelopmental Disorders in Adults

Ehninger, Dan; Li, Weidong; Fox, Kevin; Stryker, Michael P.; Silva, Alcino J.

doi:10.1016/j.neuron.2008.12.007

Cited by 179 publications

(141 citation statements)

References 93 publications

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“…Several mental retardation and neuropsychiatric conditions such as Angelman syndrome, Fragile X syndrome, and schizophrenia (37)(38)(39) are likely to require therapies that enhance the capacity for synaptic plasticity. This study therefore offers a possible avenue for developing therapies for these conditions.…”

Section: Molecular Mechanisms Underlying Accelerated Plasticity Durinmentioning

confidence: 99%

Constitutively active H-ras accelerates multiple forms of plasticity in developing visual cortex

Kaneko

Cheetham

Lee

et al. 2010

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

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Experience-dependent cortical plasticity has been studied by using loss-of-function methods. Here, we take the complementary approach of using a genetic gain-of-function that enhances plasticity. We show that a constitutively active form of H-ras (H-ras G12V ), expressed presynaptically at excitatory synapses in mice, accelerates and enhances multiple, mechanistically distinct forms of plasticity in the developing visual cortex. In vivo, H-ras G12V not only increased the rate of ocular dominance change in response to monocular deprivation (MD), but also accelerated recovery from deprivation by reverse occlusion. In vitro, H-ras G12V expression decreased baseline presynaptic release probability and enhanced presynaptically expressed longterm potentiation (LTP). H-ras G12V expression also accelerated the increase following MD in the frequency of miniature excitatory potentials, mirroring accelerated plasticity in vivo. These findings demonstrate accelerated neocortical plasticity, which offers an avenue toward future therapies for many neurological and neuropsychiatric disorders.gain of function | monocular deprivation | mouse | ocular dominance | presynaptic long-term potentiation

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Section: Molecular Mechanisms Underlying Accelerated Plasticity Durinmentioning

confidence: 99%

Constitutively active H-ras accelerates multiple forms of plasticity in developing visual cortex

Kaneko

Cheetham

Lee

et al. 2010

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

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“…Fifth, the fact that ASD and ID can be diagnosed in early childhood maximizes potential benefits of therapy because it can be started at a time when the brain is most plastic. Finally, animal studies using gene reactivation or pharmacological interventions suggest that substantial improvements can be seen even when treatments begin in adulthood (Ehninger et al 2008b). Thus, a genetic diagnosis of a developmental brain disorder need not be a "life sentence" of permanent and inexorable mental disability.…”

mentioning

confidence: 99%

Synaptic Dysfunction in Neurodevelopmental Disorders Associated with Autism and Intellectual Disabilities

Zoghbi

Bear

2012

Cold Spring Harbor Perspectives in Biology

677

589

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The discovery of the genetic causes of syndromic autism spectrum disorders and intellectual disabilities has greatly informed our understanding of the molecular pathways critical for normal synaptic function. The top-down approaches using human phenotypes and genetics helped identify causative genes and uncovered the broad spectrum of neuropsychiatric features that can result from various mutations in the same gene. Importantly, the human studies unveiled the exquisite sensitivity of cognitive function to precise levels of many diverse proteins. Bottom-up approaches applying molecular, biochemical, and neurophysiological studies to genetic models of these disorders revealed unsuspected pathogenic mechanisms and identified potential therapeutic targets. Moreover, studies in model organisms showed that symptoms of these devastating disorders can be reversed, which brings hope that affected individuals might benefit from interventions even after symptoms set in. Scientists predict that insights gained from studying these rare syndromic disorders will have an impact on the more common nonsyndromic autism and mild cognitive deficits.

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“…More importantly, genetic abnormalities affecting the imprinting of Ube3a in humans are known to cause a neurodevelopmental disorder known as Angelman syndrome (AS) (11,12), characterized by a range of symptoms including mental retardation, speech impairment, ataxia, seizures with abnormal EEG, and behavioral features, such as frequent laughter (13). Although Ube3a maternal-deficient mice have been shown to recapitulate some of the major symptoms of AS in full-grown animals (14), it is important to understand the role of Ube3a in brain development, given that neurodevelopmental disorders could arise from defects in establishment and refinement of neuronal circuits during the postnatal period (15,16).…”

mentioning

confidence: 99%

Genomic imprinting of experience-dependent cortical plasticity by the ubiquitin ligase gene Ube3a

Sato

Stryker

2010

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

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128

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A defect in the maternal copy of a ubiqutin ligase gene Ube3a can produce a neurodevelopmental defect in human children known as Angelman syndrome. We investigated the role of the maternally expressed Ube3a gene in experience-dependent development and plasticity of the mouse visual system. As demonstrated by optical imaging, rapid ocular dominance (OD) plasticity after brief monocular deprivation (MD) was severely impaired during the critical period (CP) in the visual cortex (VC) of Ube3a maternal-deficient (m−/p+) mice. Prolonged MD elicited significant plasticity in m−/ p+ mice that never matched the level seen in control animals. In older animals after the CP, 7-day MD elicited mild OD shifts in both control and m−/p+ mice; however, the OD shifts in m−/p+ mice lacked the strengthening of visual responses to the two eyes characteristic of normal adult plasticity. Anatomic effects of the maternal deficiency include reduced spine density on basal, but not apical, dendrites of pyramidal neurons in the binocular region of the VC. Imprinting of Ube3a expression was not fully established in the early postnatal period, consistent with the normal development of cortical retinotopy and visual acuity that we observed in m−/p+ mice, but was fully established by the onset of the CP. These results demonstrate that paternal and maternal genomes are not functionally equivalent for cortical plasticity, and that maternally expressed Ube3a is required for normal experience-dependent modification of cortical circuits during and after the CP.Angelman syndrome | critical period | epigenetics | ocular dominance plasticity | visual cortex

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Reversing Neurodevelopmental Disorders in Adults

Cited by 179 publications

References 93 publications

Constitutively active H-ras accelerates multiple forms of plasticity in developing visual cortex

Constitutively active H-ras accelerates multiple forms of plasticity in developing visual cortex

Synaptic Dysfunction in Neurodevelopmental Disorders Associated with Autism and Intellectual Disabilities

Genomic imprinting of experience-dependent cortical plasticity by the ubiquitin ligase gene Ube3a

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