Is lead exposure in early life an environmental risk factor for Schizophrenia? Neurobiological connections and testable hypotheses

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• 作者：Tomá ; s R. Guilarte^a ; ^{trguilarte@columbia.edu} ; Mark Opler^b ; Mikhail Pletnikov^c
• 关键词：Schizophrenia ; Lead ; Pb2+ ; Early life ; NMDA receptor ; DISC1 ; Gene&ndash ; environment interaction
• 刊名：Neurotoxicology
• 出版年：2012
• 期刊代码：35_0161813x
• 类别：pha
• 出版时间：June, 2012
• 卷：33
• 期：3
• 页码：560-574
• 文件大小：529 K

摘要

Schizophrenia is a devastating neuropsychiatric disorder of unknown etiology. There is general agreement in the scientific community that schizophrenia is a disorder of neurodevelopmental origin in which both genes and environmental factors come together to produce a schizophrenia phenotype later in life. The challenging questions have been which genes and what environmental factors? Although there is evidence that different chromosome loci and several genes impart susceptibility for schizophrenia; and epidemiological studies point to broad aspects of the environment, only recently there has been an interest in studying gene 脳 environment interactions. Recent evidence of a potential association between prenatal lead (Pb²⁺) exposure and schizophrenia precipitated the search for plausible neurobiological connections. The most promising connection is that in schizophrenia and in developmental Pb²⁺ exposure there is strong evidence for hypoactivity of the N-methyl-d-aspartate (NMDA) subtype of excitatory amino acid receptors as an underlying neurobiological mechanism in both conditions. A hypofunction of the NMDA receptor (NMDAR) complex during critical periods of development may alter neurobiological processes that are essential for brain growth and wiring, synaptic plasticity and cognitive and behavioral outcomes associated with schizophrenia. We also describe on-going proof of concept gene-environment interaction studies of early life Pb²⁺ exposure in mice expressing the human mutant form of the disrupted in schizophrenia 1 (DISC-1) gene, a gene that is strongly associated with schizophrenia and allied mental disorders.