Mild neonatal hypoxia targets synaptic maturation, disrupts adult hippocampal learning and memory and is associated with CK2-mediated dysregulation of synaptic calcium-activated potassium channel KCNN2

Since preterm survivors commonly sustain life-long memory impairment without apparent gray matter injury, we asked whether mild hypoxia alone without ischemia could persistently disrupt adult hippocampal learning and memory mechanisms without causing brain injury. We developed a preterm-equivalent 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 the expression of preterm hippocampal synaptic components was broadly targeted by mild hypoxia. Neonatal hypoxia resulted in hippocampal learning and memory deficits and abnormal maturation of CA1 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 channels, a key regulator of spike timing dependent neuroplasticity, including LTP.