Department of Pediatrics.
Obstetrics and Gynecology, and.
J Neurosci. 2019 Oct 2;39(40):7853-7871. doi: 10.1523/JNEUROSCI.1364-19.2019. Epub 2019 Aug 27.
Children who survive premature birth often exhibit reductions in hippocampal volumes and deficits in working memory. However, it is unclear whether synaptic plasticity and cellular mechanisms of learning and memory can be elicited or disrupted in the preterm fetal hippocampus. CA1 hippocampal neurons were exposed to two common insults to preterm brain: transient hypoxia-ischemia (HI) and hypoxia (Hx). We used a preterm fetal sheep model using both sexes in twin 0.65 gestation fetuses that reproduces the spectrum of injury and abnormal growth in preterm infants. Using Cavalieri measurements, hippocampal volumes were reduced in both Hx and HI fetuses compared with controls. This volume loss was not the result of neuronal cell death. Instead, morphometrics revealed alterations in both basal and apical dendritic arborization that were significantly associated with the level of systemic hypoxemia and metabolic stress regardless of etiology. Anatomical alterations of CA1 neurons were accompanied by reductions in probability of presynaptic glutamate release, long-term synaptic plasticity and intrinsic excitability. The reduction in intrinsic excitability was in part due to increased activity of the channels underlying the fast and slow component of the afterhyperpolarization in Hx and HI. Our studies suggest that even a single brief episode of hypoxemia can markedly disrupt hippocampal maturation. Hypoxemia may contribute to long-term working memory disturbances in preterm survivors by disrupting neuronal maturation with resultant functional disturbances in hippocampal action potential throughput. Strategies directed at limiting the duration or severity of hypoxemia during brain development may mitigate disturbances in hippocampal maturation. Premature infants commonly sustain hypoxia-ischemia, which results in reduced hippocampal growth and life-long disturbances in learning and memory. We demonstrate that the circuitry related to synaptic plasticity and cellular mechanisms of learning and memory (LTP) are already functional in the fetal hippocampus. Unlike adults, the fetal hippocampus is surprisingly resistant to cell death from hypoxia-ischemia. However, the hippocampus sustains robust structural and functional disturbances in the dendritic maturation of CA1 neurons that are significantly associated with the magnitude of a brief hypoxic stress. Since transient hypoxic episodes occur commonly in preterm survivors, our findings suggest that the learning problems that ensue may be related to the unique susceptibility of the hippocampus to brief episodes of hypoxemia.
早产儿存活后常表现出海马体积缩小和工作记忆缺陷。然而，尚不清楚早产儿胎脑中的突触可塑性和学习记忆的细胞机制是否可以被引发或破坏。我们将 CA1 海马神经元暴露于两种常见的早产儿脑损伤：短暂缺氧缺血（HI）和缺氧（Hx）。我们使用了一种早产胎儿绵羊模型，该模型使用了 0.65 孕期的双胞胎胎儿，重现了早产儿脑损伤和异常生长的范围。通过 Cavalieri 测量，与对照组相比，Hx 和 HI 胎儿的海马体积均减小。这种体积损失不是神经元细胞死亡的结果。相反，形态计量学显示，基底和顶树突分支的改变与全身低氧血症和代谢应激的程度有关，而与病因无关。CA1 神经元的解剖改变伴随着突触前谷氨酸释放、长时程突触可塑性和内在兴奋性的降低。内在兴奋性的降低部分是由于 Hx 和 HI 中快速和慢速后超极化的基础通道活性增加所致。我们的研究表明，即使是短暂的缺氧发作也会明显破坏海马的成熟。缺氧可能通过破坏神经元成熟导致海马动作电位通量的功能障碍，从而导致早产儿幸存者长期工作记忆障碍。旨在限制脑发育过程中缺氧持续时间或严重程度的策略可能会减轻海马成熟的干扰。早产儿通常会发生缺氧缺血，导致海马生长减少和终生学习记忆障碍。我们证明，与突触可塑性和学习记忆（LTP）的细胞机制相关的电路已经在胎儿海马中起作用。与成人不同，胎儿海马对缺氧缺血引起的细胞死亡具有惊人的抵抗力。然而，海马在 CA1 神经元树突成熟方面仍存在明显的结构和功能障碍，这与短暂缺氧应激的程度显著相关。由于早产儿幸存者中经常发生短暂的缺氧发作，我们的发现表明，随之而来的学习问题可能与海马对短暂缺氧发作的独特易感性有关。
