Prenatal Nutritional Deficiency and Risk of Adult Schizophrenia

College of Physicians and Surgeons of Columbia University, New York State Psychiatric Institute, Mailman School of Public Health, New York, NY, USA.
Schizophrenia Bulletin (Impact Factor: 8.45). 09/2008; 34(6):1054-63. DOI: 10.1093/schbul/sbn096
Source: PubMed


Converging evidence suggests that a neurodevelopmental disruption plays a role in the vulnerability to schizophrenia. The authors review evidence supporting in utero exposure to nutritional deficiency as a determinant of schizophrenia. We first describe studies demonstrating that early gestational exposure to the Dutch Hunger Winter of 1944--1945 and to a severe famine in China are each associated with an increased risk of schizophrenia in offspring. The plausibility of several candidate micronutrients as potential risk factors for schizophrenia and the biological mechanisms that may underlie these associations are then reviewed. These nutrients include folate, essential fatty acids, retinoids, vitamin D, and iron. Following this discussion, we describe the methodology and results of an epidemiologic study based on a large birth cohort that has tested the association between prenatal homocysteine, an indicator of serum folate, and schizophrenia risk. The study capitalized on the use of archived prenatal serum specimens that make it possible to obtain direct, prospective biomarkers of prenatal insults, including levels of various nutrients during pregnancy. Finally, we discuss several strategies for subjecting the prenatal nutritional hypothesis of schizophrenia to further testing. These approaches include direct assessment of additional prenatal nutritional biomarkers in relation to schizophrenia in large birth cohorts, studies of epigenetic effects of prenatal starvation, association studies of genes relevant to folate and other micronutrient deficiencies, and animal models. Given the relatively high prevalence of nutritional deficiencies during pregnancy, this work has the potential to offer substantial benefits for the prevention of schizophrenia in the population.

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    • "These studies have shown that maternal body mass and obesity prior to and during pregnancy are linked to attention deficit hyperactivity disorder (Jo et al., 2015), problems dealing with emotions (Rodriguez, 2010), eating disorders in adolescence and other executive function deficits (Van Lieshout et al., 2011, Buss et al., 2012b) as well as twothreefold increased risk of schizophrenia (Brown and Susser, 2008), increased risk of depression (Rice et al., 2007) and ASD (Bilder et al., 2013, Reynolds et al., 2014, Suren et al., 2014). Risk of childhood and adult obesity is also increased by exposure to maternal obesity and diabetes (Sullivan et al., 2015). "
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    ABSTRACT: The prenatal and postnatal early-life periods are both dynamic and vulnerable windows for brain development. During these important neurodevelopmental phases, essential processes and structures are established. Exposure to adverse events that interfere with this critical sequence of events confers a high risk for the subsequent emergence of mental illness later in life. It is increasingly accepted that the gastrointestinal microbiota contributes substantially to shaping the development of the central nervous system. Conversely, several studies have shown that early-life events can also impact on this gut community. Due to the bidirectional communication between the gut and the brain, it is possible that aberrant situations affecting either organ in early life can impact on the other. Studies have now shown that deviations from the gold standard trajectory of gut microbiota establishment and development in early life can lead to not only disorders of the gastrointestinal tract but also complex metabolic and immune disorders. These are being extended to disorders of the central nervous system and understanding how the gut microbiome shapes brain and behavior during early life is an important new frontier in neuroscience.
    Neuroscience 10/2015; DOI:10.1016/j.neuroscience.2015.09.068 · 3.36 Impact Factor
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    • "Maternal protein deficiency leads to low birth weight, which is common among people exposed prenatally to famine; there is also a well-established association between low birth weight and increased risk of schizophrenia. Using the prenatal protein deprivation (PPD) model, rats were placed on proteindeficient diets during pregnancy, and the offspring demonstrated neurotransmitter, cellular, electrophysiological, and behavioral disruptions that were associated with schizophrenia, which has been reviewed previously (Brown and Susser, 2008). These include abnormal hippocampal structures and functions, deficits in sensorimotor gating, enhanced behavioral sensitivity to acute treatment with dopamine receptor agonists and N-methyl-D-aspartic acid receptor antagonists, working memory impairments, and reduced pre-pulse inhibition (Palmer et al., 2004 2008). "
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    ABSTRACT: Epidemiological studies have identified prenatal exposure to famine as a risk factor for schizophrenia, and animal models of prenatal malnutrition display structural and functional brain abnormalities implicated in schizophrenia. Here we show that adult brain gene expression is altered in the offspring of the RLP50 rat, a recently developed animal model of prenatal malnutrition exposure. In the prefrontal cortex, offspring of RLP50 exhibit differences in neurotransmitters and olfactory associated genes expression. In the hippocampus, the differentially expressed genes are related to synaptic function and transcription regulation. DNA methylome profiling of the hippocampus also shows widespread but systematic epigenetic changes; in most cases (87%) this involves hypermethylation. Remarkably, genes encoding for plasma membrane are significantly enriched for changes in both profiling screens (P = 2.37×10(-9) and 5.36×10(-9), respectively). Interestingly, Mecp2 and Slc2a1, two genes associated with cognitive impairment, show significant down-regulation, and Slc2a1 is hypermethylated in the hippocampus of the RLP50 offspring. Collectively, our results indicate that prenatal exposure to malnutrition leads to the reprogramming of postnatal brain gene expression,and the epigenetic modifications contributed to the reprogramming. The process may impair learning and memory ability and result highly susceptible to schizophrenia. © The Author 2014. Published by Oxford University Press on behalf of CINP.
    The International Journal of Neuropsychopharmacology 10/2014; 18(4). DOI:10.1093/ijnp/pyu054 · 4.01 Impact Factor
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    • "For example, the known effect of maternal undernutrition over offspring metabolism and subsequent susceptibility to obesity later in life (Krechowec et al., 2006; Hsiao and Patterson, 2012). Several maternal insults, including maternal infection and maternal malnutrition, increase susceptibility to intrauterine growth restriction and all these factors are linked to schizophrenia, autism and cerebral palsy in the offspring (Brown and Susser, 2008; Atladóttir et al., 2010; Brown and Patterson, 2011; O’Callaghan et al., 2011). We are aware that detection of placental transcripts expression and their targets alone does not necessarily involves an effective functional interaction, therefore more studies are necessary to establish which mechanisms are implicated at the molecular level. "
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    ABSTRACT: The conserved brain design that primates inherited from early mammals differs from the variable adult brain size and species-specific brain dominances observed across mammals. This variability relies on the emergence of specialized cerebral cortical regions and sub-compartments, triggering an increase in brain size, areal interconnectivity and histological complexity that ultimately lies on the activation of developmental programs. Structural placental features are not well correlated with brain enlargement; however, several endocrine pathways could be tuned with the activation of neuronal progenitors in the proliferative neocortical compartments. In this article, we reviewed some mechanisms of eutherians maternal-fetal unit interactions associated with brain development and evolution. We propose a hypothesis of brain evolution where proliferative compartments in primates become activated by "non-classical" endocrine placental signals participating in different steps of corticogenesis. Changes in the inner placental structure, along with placenta endocrine stimuli over the cortical proliferative activity would allow mammalian brain enlargement with a concomitant shorter gestation span, as an evolutionary strategy to escape from parent-offspring conflict.
    Frontiers in Neuroanatomy 07/2013; 7:22. DOI:10.3389/fnana.2013.00022 · 3.54 Impact Factor
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