[논문]미세아교세포에서 GPR56 발현에 의한 이상 행동

김현주

doi:10.5352/jls.2023.33.6.455

[국내논문] 미세아교세포에서 GPR56 발현에 의한 이상 행동
Abnormal Behavior Controlled via GPR56 Expression in Microglia 원문보기

생명과학회지 = Journal of life science, v.33 no.6, 2023년, pp.455 - 462

김현주 (동아대학교 건강과학대학 의약생명공학과)

초록
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임신 중 감염에 의한 산모의 면역 활성화는 조현병과 자폐 스펙트럼 장애를 포함한 신경 발달 질환의 위험을 증가시킨다. 여러 연구에서 poly (I:C) 또는 LPS를 사용하여 모체 면역 활성화 유도한 자손에서 비정상적인 행동과 뇌 발달을 관찰하였다. 또한 최근 뇌에 상주하며 면역 세포로 기능하는 미세아교세포가 MIA 유발 자손의 행동 이상과 뇌 발달에 중요한 역할을 한다는 것이 보고되고 있으나 아직 메커니즘은 명확하지 않다. 본 연구에서는 GPCR의 구성원인 GPR56의 미세아교세포 특이적 억제가 행동 이상과 뇌 발달을 유발하는지 여부를 조사하였다. 먼저, MIA 유도는 발달 중인 뇌의 미세아교세포 집단에 영향을 미치지 않으나, 미세아교세포를 분리하여 GRP56의 발현을 조사한 결과, MIA 유도 태아에서 성별에 관계 없이 E14.5와 E18.5 사이에서 GPR56 발현이 억제됨을 관찰하였다. 그리고 미세아교세포 특이적 GPR56 억제는 MIA 유도 자손에게서 나타나는 사교성 결손, 반복적인 행동 패턴 및 증가된 불안 수준과 같은 비정상적인 행동을 관찰하였다. 미세아교세포 GPR56 억제 마우스에서는 MIA 유도 자손과 같은 비정상적인 피질 발달이 관찰되지 않았지만, c-fos 염색을 통해 뇌 활동이 관찰되었다. 따라서 본 연구는 미세아교세포 특이적 GPR56 결핍이 이상 행동을 유발함을 시사하며, 추후 연구를 통해 MIA 자손의 행동 결손 진단 및/ 치료 표적을 위한 바이오마커로 활용될 수 있음을 시사한다.

Abstract ▼ AI-Helper

During pregnancy, maternal immune activation (MIA) from infection increases the risk of neurodevelopmental diseases, including schizophrenia and autism spectrum disorders. MIA induced by polyinosinic-polycytidylic acid (poly (I:C)) and lipopolysaccharide (LPS) in animal experiments has led to offspring with abnormal behaviors and brain development. In addition, it has recently been reported that microglia, which reside in the brain and function as immune cells, play an important role in behavioral abnormalities and brain development in MIA-induced offspring. However, the underlying mechanism remains unclear. In this study, we investigated whether microglia-specific inhibition of GPR56, a member of the G protein-coupled receptor (GPCR) family, causes behavioral abnormalities in brain development. First, MIA induction did not affect the microglia population, but when examining the expression of microglial GRP56 in MIA-induced fetuses, GPR56 expression was inhibited between embryonic days 14.5 (E14.5) and E18.5 regardless of sex. Furthermore, microglial GPR56-suppressed mice showed abnormal behaviors in the MIA-induced offspring, including sociability deficits, repetitive behavioral patterns, and increased anxiety levels. Although abnormal cortical development such as that in the MIA-induced offspring were not observed in the microglial GPR56-suppressed mice, their brain activity was observed through c-fos staining. These results suggest that microglia-specific GPR56 deficiency may cause abnormal behaviors and could be used as a biomarker for the diagnosis and/or as a therapeutic target of behavioral deficits in MIA offspring.

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표/그림 (4)

그림 Fig. 1. Microglia population of fetal brain at E18.5 in offspring PBS or poly (I:C) injected dam and CX3CR1 cre/+, and GPR56 fx/fx; CX3CR1 cre/+ mice. Fetal brain microglia sorted by Dump^-CD45^intCD11b^high CX3CR1⁺ (n=4 each). Shows the FACs plot (A) and graph (B) of CX3CR1⁺CD11b⁺ microglia.
그림 Fig. 2. Embryonic day dependent relative GPR56 mRNA expression in fetal brain microglia from PBS- or poly (I:C)-injected mother (A). And sex-dependent relative GPR56 mRNA expression at E18.5 fetal brain microglia (B). Fetal brain microglia sorted by Dump^-CD45ⁱⁿtCD11b^highCX3CR1⁺. (n=2 PBS, n=3 poly (I:C) treated mothers). ^*p<0.05, ^**p<0.01 as calculated by t-test.
그림 Fig. 3. GPR56 deletion in brain microglia (CX3CR1⁺) promote abnormal behavior associated with MIA offspring. (n=17 CX3CR1 wt, n=14 CX3CR1 mt). A, the sociability index (% interaction or percentage of time spent investigating the social or inanimate stimulus out of the total exploration time of both objects during the 10 min sociability test) B, the time spent in the center of an open field (during the 15 min open field test) and, C, the marble burying index (the percentage of marbles buried during the 15 min marble burying test). ^*p<0.05, ^**p<0.01, ^***p<0.001 as calculated by t-test (a, b, c and e), or one-way ANOVA with Tukey test.
그림 Fig. 4. GPR56 deletion in brain microglia (CX3CR1⁺) was stained the S1DZ cortical region using STAB2 antibody and cortical activation was verified using the c-fos antibody.

AI 본문요약
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대상 데이터

The primers used were GPR56: 5'-TTGCTGCCTACCTACCTCTGCTCC-3' and 5'-AGCAGGAAGACAGCGGACAG-3' and beta-actin: 5'-CAGCAAGCAGGAGTACGATGAGTC-3' and 5'-CAGTAACAGTCCGCCTAGAAGCAC-3'.
Offspring were caged with littermates of the same sex on postnatal day 21 (PD 21). All tests were performed on the male offspring.
Seven to twelve-week old C57Bl/6N females and male mice were mated at a ratio of 2:1. On the next day, a vaginal plug was defined as embryonic day 0.

데이터처리

The results were analyzed using one-way analysis of variance (ANOVA) or unpaired Student's t-tests, as described in the figure legends

성능/효과

Similarly, autism-like behavioral patterns were observed in mice with a specific GPR56 deficiency in microglia (CX3CR1 Cre/+;GPR56 floxed/floxed mice). Thus, these results suggest that GPR56 may influence neural circuits formation during development and beyond and may affect behavior.
These results suggest that microglia-specific GPR56 gene deficiency affects autism-like behavioral phenotypes by affecting the formation of neural circuits, rather than the formation of the cortex.

후속연구

The current study confirmed that changes in GPR56 expression in microglia are involved in abnormal autism-like behavior in offspring with MIA, and in MIA-induced pathological processes during brain development. However, further mechanistic studies are required to identify the exact role of GPR56 in brain development and abnormal behavior.

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