Trends in Neurosciences
OpinionSensitive time-windows for susceptibility in neurodevelopmental disorders
Section snippets
Synaptic pathology and neurodevelopmental disorders
Development of cognitive functions requires the formation and refinement of synaptic networks of neurons in the brain. In the mammalian cortex, late embryonic and early postnatal stages of development are the periods of greatest synaptic density with significant structural and functional synaptic plasticity 1, 2. Commonly observed in both patients and animal models for many NDDs with early childhood onset are increased filopodia-to-spine ratios and abnormal protrusion densities, interpreted as
Transient age-dependent phenotypes of neuronal disorders
Clinically, the onset and progression of NDDs with intellectual disabilities and autism phenotypes can be striking. In their emergence during early childhood, NDDs are often characterized by a series of missed developmental milestones, regression of speech and motor function, and impaired social interactions 10, 11. Using genetic mouse and fly models for specific NDDs, many cellular and synaptic alterations in the mature brain have been uncovered that address mechanisms underlying symptomatic
Implications of time-windows in developmental brain disorders
The existence of impaired transient phenotypes in NDDs has implications for our understanding of developing brain circuits. Identification of sensitive time-windows where synaptic phenotypes are dysregulated in monogenic NDDs reveals a key role for specific genes at particular neurocircuit developmental stages. Given the aberrant developmental expression patterns of many genes in neurodevelopmental and autism disorders [90], there are likely to be additional defects in neurocircuit formation
Concluding remarks
Based on recently published findings, we propose the existence of sensitive windows of susceptibility for synaptic impairments in models of NDDs. Developmentally-regulated alterations in synaptic phenotypes and their consequences have not yet been fully explored (Box 1). However, we think they illustrate the dependence of specific neurocircuits during development and refinement on identified proteins misregulated in NDDs. Unraveling temporal and spatial expression profiles of genes misregulated
Acknowledgments
The authors are supported by the Nederlandse Organisatie voor Wetenschappelijke Onderzoek (NWO #917.10.372) and by the European Commission Seventh Framework Programme grant agreement FP7-People-ITN-2008-238055 (‘BrainTrain’ project). We would like to thank Guus Smit, Mustafa Sahin, Femke DeVrij and Anis Contractor for their constructive comments on earlier versions of the manuscript.
Glossary
- Amblyopia (‘lazy eye’)
- loss in one eye of the ability to see details. This is the most common cause of visual problems in children. Treatment must occur at a young age, within the critical period of the visual system, to successfully correct the impairment.
- Critical period
- a regulated time-window during which sensory experience and intrinsic neuronal activity provide information that is essential for normal development and refinement of neural circuits.
- FMRP (fragile X mental retardation protein)
References (113)
Morphometric study of human cerebral cortex development
Neuropsychologia
(1990)Rho proteins, mental retardation and the cellular basis of cognition
Trends Neurosci.
(2002)- et al.
Autism spectrum disorders: developmental disconnection syndromes
Curr. Opin. Neurobiol.
(2007) The generation of a conditional Fmr1 knock out mouse model to study Fmrp function in vivo
Neurobiol. Dis.
(2006)- et al.
Fragile X syndrome: loss of local mRNA regulation alters synaptic development and function
Neuron
(2008) Critical period plasticity is disrupted in the barrel cortex of FMR1 knockout mice
Neuron
(2010)- et al.
Neurocognitive development of attention across genetic syndromes: inspecting a disorder's dynamics through the lens of another
Prog. Brain Res.
(2011) Developmental synaptic plasticity at the thalamocortical input to barrel cortex: mechanisms and roles
Mol. Cell. Neurosci.
(2007)Anatomical pathways and molecular mechanisms for plasticity in the barrel cortex
Neuroscience
(2002)Rapid development and plasticity of layer 2/3 maps in rat barrel cortex in vivo
Neuron
(2001)
Excitatory–inhibitory balance and critical period plasticity in developing visual cortex
Prog. Brain Res.
Experience-dependent plasticity and the maturation of glutamatergic synapses
Neuron
Circuit analysis of experience-dependent plasticity in the developing rat barrel cortex
Neuron
A transcriptomic atlas of mouse neocortical layers
Neuron
Local functions for FMRP in axon growth cone motility and activity-dependent regulation of filopodia and spine synapses
Mol. Cell. Neurosci.
Rescue of behavioral phenotype and neuronal protrusion morphology in Fmr1 KO mice
Neurobiol. Dis.
Developmental expression of methyl-CpG binding protein 2 is dynamically regulated in the rodent brain
Neuroscience
Expression of MeCP2 in olfactory receptor neurons is developmentally regulated and occurs before synaptogenesis
Mol. Cell. Neurosci.
The disease progression of Mecp2 mutant mice is affected by the level of BDNF expression
Neuron
Proteomics, ultrastructure, and physiology of hippocampal synapses in a fragile X syndrome mouse model reveal presynaptic phenotype
J. Biol. Chem.
FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism
Cell
MeCP2 is a transcriptional repressor with abundant binding sites in genomic chromatin
Cell
Developmental and regional expression in the rat brain and functional properties of four NMDA receptors
Neuron
Regulation of synaptic structure and function by FMRP-associated microRNAs miR-125b and miR-132
Neuron
Increased threshold for spike-timing-dependent plasticity is caused by unreliable calcium signaling in mice lacking fragile X gene Fmr1
Neuron
STDP in the developing sensory neocortex
Front. Synaptic Neurosci.
Barrel cortex critical period plasticity is independent of changes in NMDA receptor subunit composition
Neuron
Decreased expression of the GABA(A) receptor in fragile X syndrome
Brain Res.
Decreased GABA(A) receptor expression in the seizure-prone fragile X mouse
Neurosci. Lett.
Early developmental alterations in GABAergic protein expression in fragile X knockout mice
Neuropharmacology
Impaired dendritic spine maturation in GABAA receptor alpha1 subunit knock out mice
Neuroscience
Correction of fragile X syndrome in mice
Neuron
Experience-dependent retinogeniculate synapse remodeling is abnormal in MeCP2-deficient mice
Neuron
BDNF regulates the maturation of inhibition and the critical period of plasticity in mouse visual cortex
Cell
Phenotypic checkpoints regulate neuronal development
Trends Neurosci.
Chronic pharmacological mGlu5 inhibition corrects fragile X in adult mice
Neuron
Potential therapeutic interventions for fragile X syndrome
Trends Mol. Med.
Concurrent overproduction of synapses in diverse regions of the primate cerebral cortex
Science
Rho GTPases, dendritic structure, and mental retardation
J. Neurobiol.
Rho proteins and the cellular mechanisms of mental retardation
Am. J. Med. Genet.
Dendritic anomalies in disorders associated with mental retardation
Cereb. Cortex
Regulation of dendritic spine morphology by the Rho Family of small GTPases: antagonistic roles of Rac and Rho
Cereb. Cortex
Differential effects of the Rac GTPase on Purkinje cell axons and dendritic trunks and spines
Nature
Dendritic spine ‘dysgenesis’ and mental retardation
Science
Early development in males with Fragile X syndrome: a review of the literature
Microsc. Res. Tech.
Fmr1 knockout mice: a model to study fragile X mental retardation. The Dutch–Belgian Fragile X Consortium
Cell
Which comes first in fragile x syndrome, dendritic spine dysgenesis or defects in circuit plasticity?
Neuroscientist
Fragile X mental retardation protein induces synapse loss through acute postsynaptic translational regulation
J. Neurosci.
From mRNP trafficking to spine dysmorphogenesis: the roots of fragile X syndrome
Nat. Rev. Neurosci.
Abnormal development of dendritic spines in FMR1 knock-out mice
J. Neurosci.
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