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

Abstract

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 2 + -activated potassium) channels, a 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 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 preterm survivors.