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.
No change in EGFP+ cells in Gad1-EGFP mice, but decrease in GFP+/PV+ neurons in HX mice at P15, suggesting decreased maturation. NX= normoxia; HX= hypoxia
In hypoxic mice, the GABA transporter vGAT immunoreactive terminals are decreased in layer 5 cortical pyramidal neuron cell bodies stained by the SMI32 monoclonal antibody. NX= normoxia; HX= hypoxia
Morphology of apical dendrites and spines in medial prefrontal cortex pyramidal cells after AAV-mediated tracing by AAV5-CAG-Flex-eGFP. Note abnormal thickness and branching of dendrites and abundance of thinner spines in hypoxia (HX) tissue.