Failure of neuronal homeostasis results in common neuropsychiatric phenotypes

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Abstract

Failure of normal brain development leads to mental retardation or autism in about 3% of children. Many genes integral to pathways by which synaptic modification and the remodelling of neuronal networks mediate cognitive and social development have been identified, usually through loss of function. Evidence is accumulating, however, that either loss or gain of molecular functions can be deleterious to the nervous system. Copy-number variation, regulation of gene expression by non-coding RNAs and epigenetic changes are all mechanisms by which altered gene dosage can cause the failure of neuronal homeostasis.

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Figure 1: Loss of protein or RNA function causes neurodevelopmental disorders with phenotypes overlapping those caused by gain of protein or RNA function.
Figure 2: Loss or gain of protein or RNA function results in altered neuronal homeostasis or 'imbalance'.
Figure 3: Homeostatic responses could result in a compensated neuronal network with decreased flexibility.

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Acknowledgements

In memory of our mentor, Ralph D. Feigin. We are grateful to C. Rosenmund for careful reading of the manuscript, discussions and helping us to articulate our hypothesis. We are indebted to the Howard Hughes Medical Institute, the National Institute of Neurological Disorders and Stroke (grant number 1R01 NS057819-01 to H.Y.Z., and grant numbers T32 NS43124 and 1K08 NS062711-01 to M.B.R.) and the Simons Foundation for supporting our research. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Correspondence should be addressed to the authors (mramocki@bcm.tmc.edu; hzoghbi@bcm.tmc.edu).

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