Yale School of Medicine Thesis Award Recipients — 2013

Chronic perinatal hypoxia causes a significant loss of total brain volume, brain weight, and cortical neuron number. These measures are completely reversed following recovery in normoxic conditions. Yet, the cellular and molecular mechanisms underlying this plasticity are not well understood. Here, we show that hypoxia from postnatal days 3 (P3) to 10-11 causes a 30 percent decrease in cortical neurons and a 24 percent decrease in cortical volume. Excitatory neuron numbers were completely recovered 1 month after the insult, but the mice showed a residual deficit in GABAergic interneurons. In contrast, hypoxic mice carrying a disrupted fibroblast growth factor receptor-1 (Fgfr1) gene in GFAP+ cells [Fgfr1 conditional knock-out (cKO)], showed a persistent loss of excitatory cortical neurons and an increased interneuron defect. Labeling proliferating progenitors at P17-18 revealed increased generation of cortical NeuN+ and Tbr1+ neurons in wild-type mice subjected to hypoxic insult, whereas Fgfr1 cKO failed to mount a cortical neurogenetic response. Hypoxic wild-type mice also demonstrated a two-fold increase in cell proliferation in the subventricular zone (SVZ) at P17-18 and a three-fold increase in neurogenesis in the olfactory bulb (OB) at P48-49, compared with normoxic mice. In contrast, Fgfr1 cKO mice had decreased SVZ cell proliferation and curtailed reactive neurogenesis in the OB. Thus, the activation of FGFR1 in GFAP+ cells is required for neuronal recovery after perinatal hypoxic injury. In contrast, there is incomplete recovery of inhibitory neurons following injury, which may account for persistent behavioral deficits in adult mice following early perinatal injury.