Severe inflammation in new-borns induces long-term cognitive impairment by activation of IL-1β/KCC2 signaling during early development.
Severe inflammation in new-borns induces long-term cognitive impairment by activation of IL-1β/KCC2 signaling during early development.
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DOI：
10.1186/s12916-022-02434-w
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发表时间：
2022-07-27
期刊：
影响因子：
9.3
通讯作者：
Zhou, Cheng
中科院分区：
文献类型：
--
作者：
Zhang, Donghang;Yang, Yujiao;Yang, Yaoxin;Liu, Jin;Zhu, Tao;Huang, Han;Zhou, Cheng
新生儿脓毒症可导致青春期或成年期的长期认知障碍，但其潜在的分子机制尚未完全了解。K+-Cl-协同转运体2（KCC 2）的表达在出生后早期发育过程中GABA能从去极化向超极化转变中起关键作用。在这项研究中，我们的目的是确定新生儿严重炎症诱导的认知障碍是否与早期发育过程中KCC 2的表达有关。在出生后第3天（P3）大鼠腹腔注射大剂量脂多糖（LPS，1 mg kg-1）建立新生儿严重炎症模型。采用Morris水迷宫任务和恐惧条件反射测验考察大鼠的长期认知功能。采用ELISA、RT-PCR和Western blotting检测促炎细胞因子和KCC 2的表达水平。穿孔膜片钳记录用于确定GABA能移位。新生儿严重炎症会导致大鼠长期认知障碍。同时，海马IL-1 β水平持续升高，直至P30。LPS注射后，P7-P10和P14-P16大鼠海马CA 1区锥体神经元KCC 2表达增加，超极化GABA逆转电位（EGABA）增加。特异性敲低IL-1β mRNA的表达，可在P7-P10和P14-P16恢复KCC 2和超极化EGABA的表达。因此，特异性敲低IL-1β或KCC 2表达可改善新生儿严重炎症诱导的认知障碍。海马中IL-1β的持续升高可能通过在早期发育期间上调KCC 2而诱导认知障碍。在线版本包含补充材料，可通过10.1186/s12916-022-02434-w获得。
Neonatal sepsis can induce long-term cognitive impairment in adolescence or adulthood, but the underlying molecular mechanism is not fully understood. The expression of K+-Cl– co-transporter 2 (KCC2) plays a pivotal role in the GABAergic shift from depolarizing to hyperpolarizing during early postnatal development. In this study, we aimed to determine whether neonatal severe inflammation-induced cognitive impairment was associated with the expression of KCC2 during early development. Neonatal severe inflammation was established by intraperitoneal injection of high dose lipopolysaccharide (LPS, 1 mg kg–1) in postnatal day 3 (P3) rats. The Morris water maze task and fear conditioning test were used to investigate long-term cognitive functions. ELISA, RT-PCR and Western blotting were used to examine the expression levels of proinflammatory cytokines and KCC2. Perforated patch-clamping recordings were used to determine the GABAergic shift. Neonatal severe inflammation led to long-term cognitive impairment in rats. Meanwhile, sustained elevation of interleukin-1 beta (IL-1β) levels was found in the hippocampus until P30 after LPS injection. Elevated expression of KCC2 and hyperpolarized GABA reversal potential (EGABA) were observed in CA1 hippocampal pyramidal neurons from the P7-P10 and P14-P16 rats after LPS injection. Specific knockdown of IL-1β mRNA expression rescued the elevated expression of KCC2 and the hyperpolarized EGABA at P7-P10 and P14-P16. Accordingly, specific knockdown of IL-1β or KCC2 expression improved the cognitive impairment induced by neonatal severe inflammation. Sustained elevation of IL-1β in the hippocampus may induce cognitive impairment by upregulation of KCC2 during early development. The online version contains supplementary material available at 10.1186/s12916-022-02434-w.
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影响因子：
3.3
作者：
Comim, Clarissa M.;Silva, Napoleao C.;Dal-Pizzol, Felipe
通讯作者：
Dal-Pizzol, Felipe
影响因子：
9.3
作者：
Cardoso FL;Herz J;Fernandes A;Rocha J;Sepodes B;Brito MA;McGavern DB;Brites D
通讯作者：
Brites D
影响因子：
16.2
作者：
Hübner, CA;Stein, V;Jentsch, TJ
通讯作者：
Jentsch, TJ
DOI：
10.1093/cid/ciab814
发表时间：
2022-01-20
期刊：
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
影响因子：
--
作者：
Harden LM;Leahy S;Lala SG;Paul P;Chandna J;Lowick S;Mbatha S;Jaye T;Laughton B;Ghoor A;Sithole P;Msayi J;Kumalo N;Msibi TN;Madhi SA;Lawn JE;Dangor Z
通讯作者：
Dangor Z
影响因子：
16.6
作者：
Kirmse, Knut;Kummer, Michael;Holthoff, Knut
通讯作者：
Holthoff, Knut