Perinatal Hypoxic Injury

Using mice reared in chronic hypoxic environment in the early postnatal period we model neurological and behavioral sequelae of perinatal hypoxic injury, including a decrease in cortical volume and learning deficits. The underlying cellular abnormalities include a persistent immaturity of cortical astrocytes, which retain stem cell function, as well as decreased maturation of parvalbumin- and somatostatin-expressing cortical interneurons. The interneuron deficit and the behavioral abnormalities are prevented by rearing hypoxic mice in an enriched environment. Current experiments show that dendrites of pyramidal cells are thinner, their growth stunted and receive fewer excitatory synaptic connections in hypoxic mice. Furthermore, layer 5 pyramidal cells receive fewer basket cells inhibitory terminals on their cell bodies. Hypoxia-reared mice show a prolonged decrease in mTOR/S6 kinase signaling during the critical period, which is a likely molecular mechanism for the cellular abnormalities. Future work will attempt at reverting the abnormalities using upstream regulators of mTOR/S6 kinase signaling.