Wang Qi, Shen Feng-Yan, Zou Rong, Zheng Jing-Jing, Yu Xiang, Wang Ying-Wei
Department of Anesthesiology and Intensive Care Medicine, Xinhua Hospital, College of Medicine, Shanghai Jiaotong University, Shanghai, 200092, China.
Department of Anesthesiology, Huashan Hospital, Fudan University, Shanghai, 200040, China.
Mol Brain. 2017 Jun 17;10(1):24. doi: 10.1186/s13041-017-0302-2.
The effects of general anesthetics on inducing neuronal apoptosis during early brain development are well-documented. However, since physiological apoptosis also occurs during this developmental window, it is important to determine whether anesthesia-induced apoptosis targets the same cell population as physiological apoptosis or different cell types altogether. To provide an adequate plane of surgery, ketamine was co-administered with dexmedetomidine. The apoptotic neurons in the mouse primary somatosensory cortex (S1) were quantitated by immunohistochemistry. To explore the effect of neural activity on ketamine-induced apoptosis, the approaches of Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) and an environmental enrichment (EE) were performed. Ketamine-induced apoptosis in S1 is most prominent at postnatal days 5 and 7 (P5 - P7), and becomes insignificant by P12. Physiological and ketamine-induced apoptosis follow similar developmental patterns, mostly comprised of layer V pyramidal neurons at P5 and shifting to mostly layer II to IV GABAergic neurons by P9. Changes in neuronal activity induced by the DREADD system bidirectionally regulated the pattern of ketamine-induced apoptosis, with reduced activity inducing increased apoptosis and shifting the lamination pattern to a more immature form. Importantly, rearing mice in an EE significantly reduced the magnitude of ketamine-induced apoptosis and shifted its developmental pattern to a more mature form. Together, these results demonstrate that lamination pattern and cell-type dependent vulnerability to ketamine-induced apoptosis follow the physiological apoptosis pattern and are age- and activity-dependent. Naturally elevating neuronal activity is a possible method for reducing the adverse effects of general anesthesia.
全身麻醉药在脑发育早期诱导神经元凋亡的作用已得到充分证实。然而，由于生理凋亡也发生在这个发育阶段，确定麻醉诱导的凋亡是否针对与生理凋亡相同的细胞群体或完全不同的细胞类型非常重要。为了提供足够的手术麻醉平面，将氯胺酮与右美托咪定联合使用。通过免疫组织化学对小鼠初级体感皮层（S1）中的凋亡神经元进行定量。为了探究神经活动对氯胺酮诱导凋亡的影响，采用了设计药物特异性激活的设计受体（DREADDs）和环境富集（EE）方法。氯胺酮诱导的S1凋亡在出生后第5天和第7天（P5 - P7）最为显著，到P12时变得不明显。生理凋亡和氯胺酮诱导的凋亡遵循相似的发育模式，在P5时主要由V层锥体神经元组成，到P9时转变为主要是II至IV层的γ-氨基丁酸能神经元。DREADD系统诱导的神经元活动变化双向调节氯胺酮诱导的凋亡模式，活动减少会导致凋亡增加，并将分层模式转变为更不成熟的形式。重要的是，在EE环境中饲养小鼠可显著降低氯胺酮诱导的凋亡程度，并将其发育模式转变为更成熟的形式。总之，这些结果表明，氯胺酮诱导凋亡的分层模式和细胞类型依赖性易感性遵循生理凋亡模式，且与年龄和活动有关。自然提高神经元活动是减少全身麻醉不良反应的一种可能方法。
