Prenatal hypoxia alters the tangential migration of cortical interneurons

Prenatal hypoxia is associated with a growing number of developmental disorders. However, the specific effects of hypoxia during development are poorly understood and largely under-studied. The central theme of this thesis is that hypoxic exposure during embryonic development can alter the formation of the central nervous system. The hypothesis tested is that prenatal hypoxic exposure can produce a predictable, quantifiable effect on neuronal development by altering specific signaling pathways that are known to regulate particular aspects of neuronal development.;By examining the effects of hypoxia on the expression of candidate genes, neuropilinl was identified as being sensitive to hypoxic exposure. Investigation of neuropilinl signaling in cortical interneuron progenitor cells found that chemorepulsion by the neuropilinl ligand semaphorin3A is disrupted after in vitro and in utero hypoxia. Because this activity was reported to mediate the striatal repulsion of cortical interneuron progenitor cells during tangential migration, telencephalic embryonic slice cultures were established to examine the tangential migration of cortical interneurons after in utero hypoxic exposure. The neuropilinlmediated striatal repulsion of cortical interneurons was found to be significantly decreased after hypoxic exposure. Aberrant migration into the striatum in vivo after hypoxic exposure in utero was also identified.;Examination of the mechanism through which in utero hypoxic exposure alters the striatal repulsion of migrating cortical interneurons determined that the effects of hypoxia on migration occur through a cell-intrinsic mechanism. Examination of downstream signaling focused on literature reports of cAMP sensitivity of neuropilinl signaling in axon guidance. Striatal repulsion of control cortical interneurons was found to be similarly CAMP-sensitive; and the identified loss of striatal repulsion after hypoxic exposure was shown to occur through a cAMP-sensitive mechanism.;These experiments demonstrate for the first time that prenatal exposure to hypoxia can disrupt the activity of developmentally relevant signaling mechanisms, producing specific changes in the migration of a population of neural progenitor cells. The findings of this thesis are discussed with reference to their potential contribution to human disease. Further studies are proposed to examine the long-term effects of hypoxia on interneuron development, and the potential interactions of prenatal hypoxia with genetic susceptibility to disease.