Intermittent Hypoxia Disrupts Adult Neurogenesis and Synaptic Plasticity in the Dentate Gyrus
Intermittent Hypoxia Disrupts Adult Neurogenesis and Synaptic Plasticity in the Dentate Gyrus
复制标题
DOI：
10.1523/jneurosci.1359-18.2018
复制
发表时间：
2019-02-13
影响因子：
5.3
通讯作者：
Garcia, Alfredo J., III
中科院分区：
文献类型：
--
作者：
Khuu, Maggie A.;Pagan, Chelsea M.;Garcia, Alfredo J., III
患有睡眠呼吸暂停的个体通常表现出与海马体变化一致的认知行为变化。据推测，成年神经发生在齿状回是一个持续的过程，维持正常的海马功能，在许多哺乳动物物种，包括人类。然而，慢性间歇性缺氧（IH），睡眠呼吸暂停的主要后果，海马成体神经发生的影响仍然不清楚。使用小鼠模型，我们研究了30天的IH（IH30）对成年神经发生和齿状回突触可塑性的影响。虽然IH30不影响配对脉冲易化，但IH30抑制长时程增强（LTP）。免疫组织化学实验也表明，IH扰乱成人神经发生的多个方面。IH30可增加颗粒下区Sox 2（+）神经前体细胞的增殖数量，但减少doublecortin阳性神经元的数量。与这些研究结果一致，细胞谱系追踪显示，IH 30增加了颗粒下区放射状胶质细胞的比例，但降低了成年出生的神经元在齿状回的比例。虽然在IH期间给予超氧阴离子清除剂不能防止神经祖细胞增殖，但它减轻了IH依赖的LTP抑制，并防止了成年神经元丢失。这些数据表明，IH导致活性氧物种依赖性和活性氧物种独立的成年神经发生和突触可塑性在齿状回的影响。我们的研究结果确定了海马体的细胞和神经生理学变化，这些变化可能导致睡眠呼吸暂停患者的认知和行为缺陷。
Individuals with sleep apnea often exhibit changes in cognitive behaviors consistent with alterations in the hippocampus. It is hypothesized that adult neurogenesis in the dentate gyrus is an ongoing process that maintains normal hippocampal function in many mammalian species, including humans. However, the impact of chronic intermittent hypoxia (IH), a principal consequence of sleep apnea, on hippocampal adult neurogenesis remains unclear. Using a murine model, we examined the impact of 30 d of IH (IH30) on adult neurogenesis and synaptic plasticity in the dentate gyrus. Although IH30 did not affect paired-pulse facilitation, IH30 suppressed long-term potentiation (LTP). Immunohistochemical experiments also indicate that IH perturbs multiple aspects of adult neurogenesis. IH30 increased the number of proliferating Sox2(+) neural progenitor cells in the subgranular zone yet reduced the number of doublecortin-positive neurons. Consistent with these findings, cell lineage tracing revealed that IH30 increased the proportion of radial glial cells in the subgranular zone, yet decreased the proportion of adult-born neurons in the dentate gyrus. While administration of a superoxide anion scavenger during IH did not prevent neural progenitor cell proliferation, it mitigated the IH-dependent suppression of LTP and prevented adult-born neuron loss. These data demonstrate that IH causes both reactive oxygen species-dependent and reactive oxygen species-independent effects on adult neurogenesis and synaptic plasticity in the dentate gyrus. Our findings identify cellular and neurophysiological changes in the hippocampus that may contribute to cognitive and behavioral deficits occurring in sleep apnea.