Early postnatal exposure to isoflurane causes cognitive deficits and disrupts development of newborn hippocampal neurons via activation of the mTOR pathway.
Early postnatal exposure to isoflurane causes cognitive deficits and disrupts development of newborn hippocampal neurons via activation of the mTOR pathway.
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DOI：
10.1371/journal.pbio.2001246
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发表时间：
2017-07
期刊：
影响因子：
9.8
通讯作者：
Mintz CD
中科院分区：
文献类型：
--
作者：
Kang E;Jiang D;Ryu YK;Lim S;Kwak M;Gray CD;Xu M;Choi JH;Junn S;Kim J;Xu J;Schaefer M;Johns RA;Song H;Ming GL;Mintz CD
临床和临床前研究表明，出生后早期暴露于麻醉剂可导致学习和其他认知过程的持久缺陷。这一现象背后的机制尚未阐明，目前也没有可用的治疗方法。最近的证据表明，麻醉剂可能会通过干扰大脑发育中的关键事件而导致认知功能的持续缺陷。海马体是一个对学习和记忆至关重要的大脑区域，含有大量在出生后早期发育的神经元，因此容易受到麻醉剂暴露的干扰。使用体内小鼠模型，我们证明了在出生后早期进行的临床相关的异氟烷麻醉暴露后，新产生的海马齿状回颗粒细胞神经元中树突乔木和树突棘的异常发育。此外，我们发现，异氟烷导致持续增加的活性在雷帕霉素途径的机制目标，这条途径与雷帕霉素的抑制不仅逆转了观察到的神经元发育的变化，但也大大提高了性能的空间学习和记忆的行为任务，受到损害的异氟烷暴露。我们的结论是，异氟烷通过激活一个明确的神经发育疾病通路破坏了出生后早期产生的海马神经元的发育，并且这种表型可以通过药理学抑制逆转。美国食品和药物管理局最近警告说，在产前发育的第三个三个月和生命的前3年接触麻醉和镇静药物可能会导致认知功能的持久损害。这种不良副作用发生的机制尚不清楚。在这份手稿中，我们提出了小鼠的证据，早期发育暴露于异氟烷，一种典型的全身麻醉剂，破坏了海马体神经元的适当发育，海马体是与学习和记忆相关的大脑区域。异氟烷还导致雷帕霉素（mTOR）通路的机制靶点上调，这是一种与其他神经发育认知障碍相关的信号系统。在异氟烷暴露后使用mTOR通路抑制剂治疗可使神经元发育正常化，并改善异氟烷诱导的学习障碍。我们的结论是，早期暴露于异氟烷可通过对mTOR通路的作用导致学习障碍，并且这种机制代表了一种潜在的药物靶点，以最大限度地减少麻醉剂对发育中大脑的副作用。
Clinical and preclinical studies indicate that early postnatal exposure to anesthetics can lead to lasting deficits in learning and other cognitive processes. The mechanism underlying this phenomenon has not been clarified and there is no treatment currently available. Recent evidence suggests that anesthetics might cause persistent deficits in cognitive function by disrupting key events in brain development. The hippocampus, a brain region that is critical for learning and memory, contains a large number of neurons that develop in the early postnatal period, which are thus vulnerable to perturbation by anesthetic exposure. Using an in vivo mouse model we demonstrate abnormal development of dendrite arbors and dendritic spines in newly generated dentate gyrus granule cell neurons of the hippocampus after a clinically relevant isoflurane anesthesia exposure conducted at an early postnatal age. Furthermore, we find that isoflurane causes a sustained increase in activity in the mechanistic target of rapamycin pathway, and that inhibition of this pathway with rapamycin not only reverses the observed changes in neuronal development, but also substantially improves performance on behavioral tasks of spatial learning and memory that are impaired by isoflurane exposure. We conclude that isoflurane disrupts the development of hippocampal neurons generated in the early postnatal period by activating a well-defined neurodevelopmental disease pathway and that this phenotype can be reversed by pharmacologic inhibition. The United States Food and Drug Administration has recently warned that exposure to anesthetic and sedative drugs during the third trimester of prenatal development and during the first 3 years of life may cause lasting impairments in cognitive function. The mechanisms by which this undesirable side effect occurs are unknown. In this manuscript, we present evidence in mice that early developmental exposure to isoflurane, a canonical general anesthetic, disrupts the appropriate development of neurons in the hippocampus, a brain region associated with learning and memory. Isoflurane also causes up-regulation of the mechanistic target of rapamycin (mTOR) pathway, a signaling system that has been associated with other neurodevelopmental cognitive disorders. Treatment with an inhibitor of the mTOR pathway after isoflurane exposure normalizes neuronal development and also ameliorates the impairments in learning induced by isoflurane. We conclude that early exposure to isoflurane can cause learning deficits via actions on the mTOR pathway, and that this mechanism represents a potentially druggable target to minimize the side effects of anesthetics on the developing brain.
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DOI：
10.1016/s0140-6736(15)00608-x
发表时间：
2016-01-16
期刊：
Lancet (London, England)
影响因子：
--
作者：
Davidson AJ;Disma N;de Graaff JC;Withington DE;Dorris L;Bell G;Stargatt R;Bellinger DC;Schuster T;Arnup SJ;Hardy P;Hunt RW;Takagi MJ;Giribaldi G;Hartmann PL;Salvo I;Morton NS;von Ungern Sternberg BS;Locatelli BG;Wilton N;Lynn A;Thomas JJ;Polaner D;Bagshaw O;Szmuk P;Absalom AR;Frawley G;Berde C;Ormond GD;Marmor J;McCann ME;GAS consortium
通讯作者：
GAS consortium
影响因子：
16.6
作者：
Chen Q;Zhang H;Liu Y;Adams S;Eilken H;Stehling M;Corada M;Dejana E;Zhou B;Adams RH
通讯作者：
Adams RH
影响因子：
64.5
作者：
Duan, Xin;Chang, Jay H.;Song, Hongjun
通讯作者：
Song, Hongjun
影响因子：
8.8
作者：
Briner, Adrian;De Roo, Mathias;Vutskits, Laszlo
通讯作者：
Vutskits, Laszlo
影响因子：
3.7
作者：
DiMaggio C;Sun LS;Kakavouli A;Byrne MW;Li G
通讯作者：
Li G