Elsevier

Biological Psychiatry

Volume 68, Issue 4, 15 August 2010, Pages 314-319
Biological Psychiatry

Review
Early Life Programming and Neurodevelopmental Disorders

https://doi.org/10.1016/j.biopsych.2010.05.028Get rights and content

For more than a century, clinical investigators have focused on early life as a source of adult psychopathology. Early theories about psychic conflict and toxic parenting have been replaced by more recent formulations of complex interactions of genes and environment. Although the hypothesized mechanisms have evolved, a central notion remains: early life is a period of unique sensitivity during which experience confers enduring effects. The mechanisms for these effects remain almost as much a mystery today as they were a century ago. Recent studies suggest that maternal diet can program offspring growth and metabolic pathways, altering lifelong susceptibility to diabetes and obesity. If maternal psychosocial experience has similar programming effects on the developing offspring, one might expect a comparable contribution to neurodevelopmental disorders, including affective disorders, schizophrenia, autism, and eating disorders. Due to their early onset, prevalence, and chronicity, some of these disorders, such as depression and schizophrenia, are among the highest causes of disability worldwide according to the World Health Organization 2002 report. Consideration of the early life programming and transcriptional regulation in adult exposures supports a critical need to understand epigenetic mechanisms as a critical determinant in disease predisposition. Incorporating the latest insight gained from clinical and epidemiological studies with potential epigenetic mechanisms from basic research, the following review summarizes findings from a workshop on Early Life Programming and Neurodevelopmental Disorders held at the University of Pennsylvania in 2009.

Section snippets

Schizophrenia

Prenatal and early life events have been associated with the development of schizophrenia. In support of a temporal specificity to the effects of stress on long-term outcome in neurodevelopmental disorders, a recent epidemiological study reported a significant association between maternal stress experienced during the first trimester of pregnancy with an increased risk of schizophrenia in male offspring (7). Prospective birth cohort studies have suggested that such stress exposures act by

Programming Effects of Maternal Diet and Early Nutrition

Not surprisingly, maternal nutrition alone or in combination with other prenatal determinants has been identified as a likely factor involved in the programming of offspring disease risk (55). Recent epidemiological studies from the Dutch Hunger Winter and the 1959 to 1961 Chinese famines have provided convincing evidence that prenatal undernutrition increases the risk of schizophrenia twofold in adult life (56, 57). A variety of scenarios may explain these outcomes, including epigenetic

What Does Sex Have to Do with It?

One area of emphasis that has not been well examined or discussed in early life programming is that of the role or involvement of sex in disease vulnerability, presentation, and outcome. Why do some neurodevelopmental disorders predominate in male subjects and others in female subjects? Numerous neurodevelopmental diseases exhibit such a sex bias: for example, women present with affective disorders at two to three times the rate of men, autism affects four times as many boys as girls, and the

Epigenetic Mechanisms for Stable Behavioral Modification

Studies in adult animal models have used molecular and pharmacological methodologies to identify potential genes and mechanisms involved in disease programming. For example, histone deacetylase (HDAC) inhibitors, which are thought to promote gene transcription, produce antidepressant-like effects in rodent models of chronic stress such as social defeat (78). Chronic exposure of inbred mice to social defeat stress induces long-lasting behavioral abnormalities that are reminiscent of depression

Conclusions

At the crossroads of the developing brain and the perturbations poised to promote any deviation from this norm may lay the programming events contributing to disease susceptibility or resistance. Studies aimed at this level afford us a great opportunity to define disease mechanisms and identify novel targets in therapy and prevention. The interaction of the clinical, epidemiological, and basic science communities is essential in evaluation of study outcomes and in defining future directions and

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