Ž . Developmental Brain Research 105 1998 287–293 Research report Chronic hypoxemia causes extracellular glutamate concentration to increase in the cerebral cortex of the near-term fetal sheep Janice L. Henderson a , James D. Reynolds b , Franklin Dexter b , Barry Atkins b , Jim Hrdy b , Dan Poduska b , Donald H. Penning b, ) a Obstetrical Anesthesia Research Laboratory, Department of Obstetrics and Gynecology, UniÕersity of Iowa, College of Medicine, Iowa City, IA, USA b Obstetrical Anesthesia Research Laboratory, Department of Anesthesia, UniÕersity of Iowa, College of Medicine, Iowa City, IA, USA Accepted 21 October 1997 Abstract Fetal hypoxia is an important cause of neurologic morbidity and mortality. Hypoxia-induced increase in extracellular glutamate concentration can lead to excitotoxic neuronal death in adults. The objective of this study was to test whether chronic fetal hypoxemia increases extracellular glutamate concentration in the unanesthetized intact cerebral cortex of the near-term fetal sheep. Microdialysis probes were implanted into the parasagittal parietal cortex and periventricular white matter of near-term fetal sheep. At 124 "1 days of gestation, extracellular glutamate concentration was determined before and during 24 h of fetal hypoxemia. Chronic hypoxemia was produced by tightening a vascular occluder placed around the maternal common iliac artery. Larger decreases in fetal arterial oxygen Ž content were associated with larger increases in extracellular glutamate concentration in the parietal cortex Kendall’s t s0.81, N s7, . p s0.005 . No such relationship was detected in the periventricular white matter. Chronic hypoxemia increases extracellular glutamate concentration in the intact cerebral cortex of the unanesthetized near-term fetal sheep. q 1998 Elsevier Science B.V. Keywords: Cerebral cortex; Glutamate; Hypoxia; Microdialysis; Ovine fetus; Periventricular white matter 1. Introduction Fetal hypoxemia is an important cause of neurologic w x morbidity and perinatal mortality 23 . Chronic fetal hy- Ž poxemia can be caused by maternal hypoxia e.g., during . an asthma exacerbation or decreased uterine blood flow Ž . e.g., during severe preeclampsia . In survivors, hypox- emia can produce severe postnatal neurologic and behav- ioral deficits such as mental retardation, learning disabili- w x ties and epilepsy 13 . Ž . In the adult central nervous system CNS , high synap- tic concentrations of the excitatory neurotransmitter L- glutamate contributed to ischemia-induced neuronal death w x 12 . Glutamate also plays a key role in CNS development w x 11 . Glutamate can regulate neuronal survival, dendritic and axonal growth, synaptogenesis, and activity-dependent ) Corresponding author. Division of Women’s Anesthesia, Department of Anesthesiology, Duke University Medical Center, Box 3094, Durham, NC 27710, USA. Fax: q 1-919-681-7022; E-mail: penni008@mc.duke.edu synaptic plasticity in many regions of the developing brain. Overactivation of the glutamate neuronal system can dis- w x rupt development 7,11 . The effect of fetal hypoxemia on cortical glutamate efflux 1 is poorly understood. Animal models of ischemic hypoxia are not applicable, because fetal cerebral blood wx flow increases during most clinically relevant hypoxia 6 . wx Hagberg et al. 5 showed that fetal hypoxemia causes extracellular cerebral cortical glutamate concentration to increase, albeit in an exteriorized fetus under general anes- thesia. In this study, we used chronic in utero cerebral microdialysis to test the hypothesis that chronic fetal hy- poxemia increases extracellular glutamate concentration in the intact cerebral cortex of the unanesthetized near-term fetal sheep. 1 Efflux is defined as the net result of release of glutamate into the extracellular space from neurons, glia, etc., less reuptake by the same. As such, increased levels could come from increased release or impaired uptake. 0165-3806r98r$19.00 q 1998 Elsevier Science B.V. All rights reserved.