Opinion
Sensitive time-windows for susceptibility in neurodevelopmental disorders

https://doi.org/10.1016/j.tins.2012.03.005Get rights and content

Many neurodevelopmental disorders (NDDs) are characterized by age-dependent symptom onset and regression, particularly during early postnatal periods of life. The neurobiological mechanisms preceding and underlying these developmental cognitive and behavioral impairments are, however, not clearly understood. Recent evidence using animal models for monogenic NDDs demonstrates the existence of time-regulated windows of neuronal and synaptic impairments. We propose that these developmentally-dependent impairments can be unified into a key concept: namely, time-restricted windows for impaired synaptic phenotypes exist in NDDs, akin to critical periods during normal sensory development in the brain. Existence of sensitive time-windows has significant implications for our understanding of early brain development underlying NDDs and may indicate vulnerable periods when the brain is more susceptible to current therapeutic treatments.

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)

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