Ischemic perinatal stroke (IPS) affects 1 in 2,300-5,000 live births. Despite a survival rate >95%, approximately 60% of IPS infants develop motor and cognitive impairments. Given the importance of axonal growth and synaptic plasticity in neurocognitive development, our objective was to identify the molecular pathways underlying IPS-associated synaptic dysfunction using a mouse model. IPS was induced by unilateral ligation of the common carotid artery of postnatal day 10 (P10) mice. Five days after ischemia, sensorimotor and motor functions were assessed by vibrissae-evoked forepaw placement and the tail suspension test respectively, showing evidence of greater impairments in male pups than in female pups. Twenty-four hours after ischemia, both hemispheres were collected and synaptosomal proteins then prepared for quantification, using isobaric tags for relative and absolute quantitation. Seventy-two of 1,498 qualified proteins were altered in the ischemic hemisphere. Ingenuity Pathway Analysis was used to map these proteins onto molecular networks indicative of reduced neuronal proliferation, survival, and synaptic plasticity, accompanied by reduced PKCα signaling in male, but not female, pups. These effects also occurred in the non-ischemic hemisphere when compared with sham controls. The altered signaling effects may contribute to the sex-specific neurodevelopmental dysfunction following IPS, highlighting potential pathways for targeting during treatment.

中文翻译：

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围产期缺血改变突触体蛋白的整体表达，这对发育中的小鼠大脑的神经可塑性至关重要。


缺血性围产期卒中 (IPS) 影响每 2,300-5,000 名活产婴儿中就有 1 人患有缺血性围产期中风 (IPS)。尽管存活率 >95%，但大约 60% 的 IPS 婴儿会出现运动和认知障碍。鉴于轴突生长和突触可塑性在神经认知发育中的重要性，我们的目标是使用小鼠模型确定 IPS 相关突触功能障碍的分子途径。通过单侧结扎出生后第 10 天 (P10) 小鼠的颈总动脉来诱导 IPS。缺血五天后，分别通过触须诱发的前爪放置和尾部悬吊试验评估感觉运动和运动功能，显示雄性幼崽比雌性幼崽有更大的损伤。缺血后二十四小时，收集两个半球，然后准备用于定量的突触体蛋白，使用同量异位标签进行相对和绝对定量。 1,498 种合格蛋白质中的 72 种在缺血半球中发生了改变。 Ingenuity Pathway Analysis 用于将这些蛋白质映射到分子网络上，表明雄性幼犬的神经元增殖、存活和突触可塑性降低，同时 PKCα 信号传导降低，但雌性幼犬则不然。与假手术对照相比，这些效应也发生在非缺血半球中。改变的信号效应可能会导致 IPS 后性别特异性神经发育功能障碍，突出显示治疗期间靶向的潜在途径。