Written by Zhang Donghang

Editor in charge ︱ Wang Sizhen

Editor︱Yang Binwei

Sepsis is the leading cause of neonatal death in the neonatal intensive care unit (NICU) [1]

Studies have shown that persistent intracranial inflammation caused by sepsis is an important cause of cognitive impairment

Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the adult central nervous system

On July 27, 2022, researcher Zhou Cheng's research group from West China Hospital of Sichuan University published a paper entitled "Severe inflammation in new-borns induces long-term cognitive impairment by activation of IL-1β/KCC2 signaling during early development" in BMC Medicine research

First, the authors established a neonatal sepsis model by intraperitoneal injection of LPS in rats on day 3 (P3)

Figure 1: Neonatal sepsis causes cognitive impairment in adolescent rats

(Image source: Zhang et al.

Next, the authors explored the changes in the expression levels of inflammatory factors in the brain caused by sepsis
.

The results showed that the levels of TNF and IL-6 in peripheral blood and hippocampus only increased transiently after sepsis, while the expression of IL-1β in hippocampus continued to be high for at least 30 days (Figure 2)
.

This indicates that IL-1β may be the dominant factor in maintaining the persistence of intracranial inflammation caused by sepsis
.

Figure 2: Neonatal rat sepsis causes persistent elevation of IL-1β expression in rat hippocampus
.

(Image source: Zhang et al.
, BMC Med, 2022)

Then, by specifically knocking down the expression of IL-1β in the hippocampus, the authors found that it could improve the long-term cognitive impairment caused by sepsis (Fig.
3), directly confirming that IL-1β is the key to the cognitive impairment caused by sepsis factor
.

Figure 3: Persistently high expression of IL-1β in the hippocampus causes long-term cognitive impairment
.

(Image source: Zhang et al.
, BMC Med, 2022)

Further, the authors explored whether KCC2 mediates IL-1β-induced cognitive impairment
.

It was found that sepsis could up-regulate the expression of KCC2 in the hippocampus of P7 and P14 rats (Fig.
4B)
.

In vivo knockdown of hippocampal IL-1β expression can inhibit sepsis-induced increase in KCC2 expression; in vivo knockdown of hippocampal KCC2 expression can ameliorate sepsis-induced cognitive impairment (Figure 4E-L)
.

It is confirmed that the activation of IL-1β-KCC2 pathway is one of the key pathways of sepsis-induced long-term cognitive impairment
.

Figure 4: KCC2 is one of the downstream molecules that mediate IL-1β-induced long-term cognitive impairment
.

(Image source: Zhang et al.
, BMC Med, 2022)

Finally, using the perforated patch-clamp technique, the authors directly examined the effect of sepsis on the transition of GABA function in early development
.

It was found that sepsis induced hyperpolarization of GABA function in early developmental P7-10 (Fig.
5B-E) and P14-16 (Fig.
5F-I), i.
e.
, premature maturation, whereas knockdown of IL-1β or KCC2 mRNA can inhibit this phenomenon (Fig.
5M-S)
.

_{Figure 5: Sepsis in neonatal rats induces E GABA} hyperpolarization in hippocampal pyramidal neurons
.

(Image source: Zhang et al.
, BMC Med, 2022)

Conclusion and discussion, inspiration and prospect of the article In summary, this study confirmed through a series of research methods: neonatal sepsis can induce early maturation of GABA function in early development by activating the IL-1β-KCC2 pathway in the hippocampus, causing distant Period cognitive impairment
.

Therefore, IL-1β/KCC2, or inhibiting excessive GABA function may become new targets for preventing or treating long-term cognitive impairment caused by sepsis
.

However, since the expression of KCC2 and E _GABA had returned to normal at the time point of behavioral detection (P30), the factors leading to cognitive impairment at this time deserve further study
.

At the same time, whether the cognitive impairment caused by abnormal GABA function during development is gender-dependent needs to be further confirmed
.

Original link: https://doi.
org/10.
1186/s12916-022-02434-w.

Corresponding authors: Zhou Cheng (left), Huang Han (middle); first author: Zhang Donghang (right)
.

(Photo provided by: Researcher Zhou Cheng’s team at West China Hospital, Sichuan University)

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End of this article