Impaired Organization of GABAergic Neurons Following Prenatal Hypoxia

Abstract

Several conditions related to the intrauterine environment are associated with neuropsychiatric conditions in later life. In humans, approximately 2% of infants are exposed to perinatal hypoxia-ischemia or prolonged anoxic insult, a condition to which very low birth weight preterm infants exhibit the highest susceptibility. Analyses of postmortem tissue link some presentations of these conditions to changes in GABA pathway functionality in the brains of affected subjects. Using animal models of early-life hypoxia-ischemia, losses of particular interneuron populations were reported. We hypothesize that the origin of GABAergic cell loss is in the mispositioning of neurons during the formation of the cerebral cortex. Here we report that in C57 black mice exposed to hypoxic conditions (9% O₂; 3% CO₂), 22-26% of cell loss was detected in the cortical plate as early as four days after the hypoxic event. Moreover, the surviving cells failed to populate the proper layers in the developing cortex. Differential sensitivities were observed in neurons that originated from different germinal zones. A significant effect of GABAergic cell location along the anterior-posterior and medio-lateral axes on neuron sensitivity to hypoxia was detected. Finally, changes in guidance molecules in the developing cortex, including increases in hypoxia-inducible factor 1-alpha levels and intracellular distribution, decreases in reelin levels in the cortical plate and altered organization of radial glia, were observed. These changes in the molecular landscape of the immediate environment of the immature neurons may contribute to the observed outcomes in neuronal migration to, and establishment in, the correct cortical layers. We suggest that the interneuron loss may be related to these early events.

Keywords: GABA; interneuron; maternal hypoxia; migration; neurogenesis.