Immediate and delayed decrease of long term potentiation and memory deficits after neonatal intermittent hypoxia

Abstract

Apnea of prematurity is a common clinical condition that occurs in premature infants and results in intermittent hypoxia (IH) to brain and other organs. While short episodes of apnea are considered of no clinical significance, prolonged apnea with bradycardia and large oxygen desaturation is associated with adverse neurological and cognitive outcome. The mechanisms of cognitive deficits in IH are poorly understood. We hypothesized that brief but multiple episodes of severe oxygen desaturation accompanied by bradycardia may affect early and late synaptic plasticity and produce long-term cognitive deficits. C57BL/6 mouse pups were exposed to IH paradigm consisting of alternating cycles of 5% oxygen for 2.5 min and room air for 5-10 min, 2 h a day from P3 to P7. Long term potentiation (LTP) of synaptic strength in response to high frequency stimulation in hippocampal slices were examined 3 days and 6 weeks after IH. LTP was decreased in IH group relative to controls at both time points. That decrease was associated with deficits in spatial memory on Morris water maze and context fear conditioning test. Hypomyelination was observed in multiple gray and white matter areas on in vivo MRI using micromolecule proton fraction and ex vivo diffusion tensor imaging. No difference in caspase labeling was found between control and IH groups. We conclude that early changes in synaptic plasticity occurring during severe episodes of neonatal IH and persisting to adulthood may represent functional and structural substrate for long term cognitive deficits.

Keywords: Hypomyelination; Intermittent hypoxemia; Memory deficits; Synaptic plasticity.