Hippocampal constitutive nitric oxide synthase in the guinea pig: Ontogeny and effects of chronic prenatal ethanol exposure in the near-term fetus

Ethanol is a teratogen and can adversely affect hippocampal development. A postulated mechanism of ethanol teratogenesis involving the hippocampus is suppression of the L-glutamate (Glu) - NMDA receptor - nitric oxide synthase (NOS) system. Ethanol suppresses Glu release and chronic prenatal ethanol exposure decreases the number and alters the function of NMDA receptors in the hippocampus. However, the effect of chronic prenatal ethanol exposure on NOS has not been investigated. The overall goal was to test the hypothesis that chronic prenatal ethanol exposure, via maternal oral administration of 4 g ethanol/kg maternal body weight/day throughout gestation, suppresses hippocampal NOS in the near-term fetal guinea pig. The first objective was to characterize the ontogeny of NOS activity and NOS I and III protein expression. NOS activity increased throughout development to adult level by postnatal day (PD) 21. NOS I protein expression was low at gestational day (GD) 50 and increased to adult level by GD 62. NOS III protein expression was low prenatally and gradually increased to highest level in the adult that reflected the ontogeny of NOS activity. The second objective was to determine the effect of chronic prenatal ethanol exposure on hippocampal NOS in the near-term fetal guinea pig. The ethanol regimen decreased fetal body, brain and hippocampal weights, and decreased NOS activity. Suppression of NOS activity was not the result of loss of NOS-containing neurons or decreased NOS I and/or III protein expression. It is conceivable that ethanol alters post-translational modifications to NOS I and III proteins resulting in decreased activity. Ethanol exposure did not decrease hippocampal CA1 or CA3 pyramidal neurons in the near-term fetus; however, a previous study demonstrated that this ethanol regimen decreases the number of CA1 pyramidal neurons by 25% in adulthood. It is proposed that chronic ethanol exposure suppresses the Glu - NMDA receptor - NOS system prenatally, which causes hippocampal dysfunction thereby resulting in loss of CA1 pyramidal neurons in postnatal life.