Mild Neonatal Hypoxia Targets Synaptic Maturation, Disrupts Adult Hippocampal Learning and Memory, and Is Associated with CK2-Mediated Loss of Synaptic Calcium-Activated Potassium Channel KCNN2 Activity.

Preterm infants frequently sustain brief hypoxic insults of unclear clinical significance. Since preterm survivors commonly sustain lifelong memory impairment without apparent gray matter injury, we tested whether mild hypoxia alone without ischemia could persistently disrupt adult hippocampal learning and memory mechanisms without causing brain injury. We developed a neonatal mouse model of mild hypoxia that generated clinically relevant oxygen desaturation, but without responses typically associated with hypoxia-ischemia including bradycardia, seizures, neuroinflammation, and neuronal or glial degeneration. RNA transcriptomic studies identified that expression of immature hippocampal synaptic components was broadly targeted by mild hypoxia. Neonatal hypoxia resulted in hippocampal learning and memory deficits and abnormal maturation of CA1 (cornu ammonis 1) neurons that persisted into adulthood. Memory deficits were accompanied by reduced adult hippocampal CA3→CA1 synaptic strength and LTP and abolished synaptic activity of calcium-sensitive SK2 (small conductance Ca