The causes of schizophrenia remain elusive, though there is strong evidence that pre- and perinatal complications, including prenatal exposure to infection, increase the risk of a person ultimately developing schizophrenia. In spite of their etiological importance, not only for schizophrenia, but also for other neurodevelopmental diseases (including lissencephaly, neural tube defects, autism, and mental retardation), the mechanisms by which clinical pre- and perinatal risk factors such as infection alter the developing brain have remained largely unstudied. It is hypothesized that pro-inflammatory cytokines, including interleukin-lbeta (IL-1B), interleukin 6 (IL-6), and tumor necrosis factor-alpha (TNF-A), generated by the maternal, and/or placental immune system in response to infection play a key role in the association between prenatal infection and schizophrenia. Amniotic fluid and fetal cord blood levels of cytokines are increased in human pregnancies complicated by infection. IL-1B, IL-6, and TNF-A can all be neurotoxic to developing cortical neurons; the actions of cytokines on developing neurons are consistent with abnormalities of cortical neuron number, size, and """"""""connectivity"""""""" found in the brains of patients with schizophrenia. There is also evidence that cytokines regulate more classic neurotrophic factors. The goal of this research is to characterize cytokine (IL-1B, IL-6, TNF-A) and neurotrophic factor [brain derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), nerve growth factor (NGF)] responses to prenatal infection and to study cytokine regulation of cortical neuron development. A clinical study of amniotic fluid obtained at amniocentesis from human pregnancies with and without prior exposure to infection will be used to determine cytokine and neurotrophic factor response to prenatal infection. Pre-clinical studies in a rat model of early infection (E. coli lipopolysaccaride exposure) will investigate the regulation of cytokine and neurotrophic factor (BDNF, NT-3, NGF) protein in the developing cortex. In addition, in vitro primary cell culture techniques will be used to study cytokine regulation of embryonic cortical neuron survival, growth, and synapse formation. These studies will provide a better understanding of how this clinically important risk factor for schizophrenia and other neurodevelopmental disorders can alter cortical neuron development, and may ultimately provide a rational basis on which to develop preventative treatment strategies.
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