Hippocampal SPAR Activation Of Neonatal Mice Subjected To Intermittent Hypoxia Enhances Spatial Learning And Memory

In our previous investigation,neonatal exposure to mild intermittent hypoxia enhances the amplitude of hippocampal long-term potentiation(LTP) and spatial learning and memory in mice,but the mechanism is still unknown.SPAR(a spine-associated RapGAP) forms a complex with PSD-95 and NMDA receptors (NMDARs) and morphologically regulates dendritic spines that may contribute to learning and memory.Here,we showed that neonatal exposure to IH uniquely led to the up-regulation of hippocampal SPAR expression during postnatal development in mice.To test whether this up-regulation is associated with the enhancement of spatial learning and memory, the dorsal hippocampi of bilaterally cannulated mice were infused with SPAR antisense, missense,or PBS.The SPAR antisense treatment time-dependently disrupted hippocampal SPAR expression.The acquisition of the Morris water maze was impaired, but visual acuity test and swimming speed were unchanged in SPAR antisense treated mice.Furthermore,the memory retention of SPAR antisense treated mice was decreased after the training of the water maze compared with controls.The working memory was also impaired in SPAR knockdown mice by measuring in the eight-arm maze.In the hippocampal SPAR knockdown mice,basal synaptic transmission was not affected,while LTP was significantly attenuated.Our finding suggests intermittent hypoxia enhances spatial learning by up-regulating the SPAR expression.IGF-I has been identified as a neurotrophic factor and the expression levels IGF family proteins are increased in brain,which undergoes stress and/or injury.The IGF-I protein expression was up-regulated during the four weeks hypoxia period;the IGF-IR was up-regulated at postnatal 28(P28) and P35;and the IGFBP-2 was up-regulated from P14 to P35 in the hippocampus of IH-treated mice compared with control. Furthermore,IGFBP-2 antibody was infused into the dorsal hippocampi of bilaterally cannulated mice.Hippocampal SPAR expression was down-regulated by IGFBP-2 antibody treatment both in water maze training-undergoing mice and without water maze training ones.Compared with IgG-treated controls,the performance of water maze was impaired in IGFBP-2 antibody-treated mice.The water maze training increased the IGF-I mRNA expression in hippocampus.However,the IGF-IR antagonist infusion could not down-regulate the expression of SPAR.This study provides the first evidence that SPAR is functionally required for synaptic plasticity and spatial learning and memory in IH treated and normoxic mice.The IH induced up-regulation of SPAR expression may result from increased expression of IGFBP-2.