Integrated Excitatory/Inhibitory Imbalance and Transcriptomic Analysis Reveals the Association between Dysregulated Synaptic Genes and Anesthetic-Induced Cognitive Dysfunction.
Integrated Excitatory/Inhibitory Imbalance and Transcriptomic Analysis Reveals the Association between Dysregulated Synaptic Genes and Anesthetic-Induced Cognitive Dysfunction.
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DOI：
10.3390/cells11162497
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发表时间：
2022-08-11
期刊：
影响因子：
6
通讯作者：
Bai, Xiaowen
中科院分区：
文献类型：
--
作者：
Yan, Yasheng;Logan, Sarah;Liu, Xiaojie;Chen, Bixuan;Jiang, Congshan;Arzua, Thiago;Ramchandran, Ramani;Liu, Qing-song;Bai, Xiaowen
来自人类流行病学和动物研究的新证据表明，发育麻醉神经毒性可能导致长期的认知缺陷和行为问题。然而，其潜在机制在很大程度上仍然未知。我们对出生后第60天（P60）接受丙泊酚暴露的出生后第7天（P7）小鼠的海马组织突触活动进行了电生理分析，并对24，881 mRNA表达进行了转录组学分析。我们发现，与对照组小鼠相比，异丙酚暴露的P60小鼠海马神经元发育表现出E/I失衡，表现为兴奋减少和抑制增加。我们发现，丙泊酚暴露于P7导致P60小鼠海马中317个mRNA的异常表达，其中包括23个突触相关基因。各种生物信息学分析表明，这些异常表达的突触基因与突触活动和可塑性、E/I平衡、行为和认知障碍的功能和发育相关。我们的研究结果表明，E/I平衡的改变可能构成了丙泊酚诱导的小鼠长期学习和记忆障碍的机制。这些与突触功能相关的失调基因的转录组学和生物信息学分析为通过恢复E/I平衡和修饰突触基因表达来开发针对麻醉性神经变性的治疗策略铺平了道路。
Emerging evidence from human epidemiologic and animal studies has demonstrated that developmental anesthesia neurotoxicity could cause long-term cognitive deficits and behavioral problems. However, the underlying mechanisms remain largely unknown. We conducted an electrophysiological analysis of synapse activity and a transcriptomic assay of 24,881 mRNA expression on hippocampal tissues from postnatal day 60 (P60) mice receiving propofol exposure at postnatal day 7 (P7). We found that developmentally propofol-exposed P60 mouse hippocampal neurons displayed an E/I imbalance, compared with control mice as evidenced by the decreased excitation and increased inhibition. We found that propofol exposure at P7 led to the abnormal expression of 317 mRNAs in the hippocampus of P60 mice, including 23 synapse-related genes. Various bioinformatic analyses revealed that these abnormally expressed synaptic genes were associated with the function and development of synapse activity and plasticity, E/I balance, behavior, and cognitive impairment. Our findings suggest that the altered E/I balance may constitute a mechanism for propofol-induced long-term impaired learning and memory in mice. The transcriptomic and bioinformatic analysis of these dysregulated genes related to synaptic function paves the way for development of therapeutic strategies against anesthetic neurodegeneration through the restoration of E/I balance and the modification of synaptic gene expression.
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影响因子：
3.7
作者：
Gatto CL;Broadie K
通讯作者：
Broadie K
影响因子：
8.8
作者：
Jevtovic-Todorovic V
通讯作者：
Jevtovic-Todorovic V
影响因子：
5.7
作者：
Bai X;Yan Y;Canfield S;Muravyeva MY;Kikuchi C;Zaja I;Corbett JA;Bosnjak ZJ
通讯作者：
Bosnjak ZJ
影响因子：
5.6
作者：
Jiang C;Arzua T;Yan Y;Bai X
通讯作者：
Bai X
影响因子：
5.1
作者：
Diana, Paolo;Joksimovic, Srdjan M.;Jevtovic-Todorovic, Vesna
通讯作者：
Jevtovic-Todorovic, Vesna