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 life-long 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 mixed sex 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 the 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 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 and memory encoding. Structural illumination microscopy revealed reduced synaptic density without altered synaptic SK2 distribution. Persistent loss of SK2 activity was mediated by increased CK2 phosphorylation of synaptic calmodulin and restored by CK2 blockade. Clinically relevant mild hypoxia in neonatal mice is thus sufficient to disrupt hippocampal maturation into adulthood independently of cerebral gray or white matter injury and trigger persistent loss of synaptic potassium SK2 channel activity that disrupts excitatory synaptic function. Our findings suggest that neonatal hypoxia contributes to the broad spectrum of neurobehavioral, cognitive and learning disabilities that paradoxically persist into adulthood without overt gray matter injury in survivors of preterm birth.<b>Significance Statement</b> After preterm birth, isolated mild hypoxic events occur commonly during intensive care, but their long-term impact on neurodevelopmental outcomes remains unclear. Prior studies have mostly focused on the effect of severe or prolonged hypoxic events associated with brain injury, inflammation and seizures. We identified that neonatal brain development coincides with a maturational window when mild hypoxia is sufficient to broadly target immature hippocampal synaptic components with resultant disturbances in learning and memory mechanisms that persist into adulthood without the injurious consequences of more severe hypoxia or hypoxia-ischemia. Our findings suggest that hypoxia-dependent synaptic dysmaturation may contribute significantly to adverse outcomes in preterm survivors and raises the potential for alternative therapeutic strategies focused on re-tuning of synaptic activity to enhance learning and memory.