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氯胺酮调节精神分裂症相关蛋白1/糖原合酶激酶-3β的相互作用紊乱。

Ketamine modulates disrupted in schizophrenia-1/glycogen synthase kinase-3β interaction.

作者信息

Liu Jia-Ren, Han Xiao Hui, Yuki Koichi, Soriano Sulpicio G

机构信息

Department of Clinical Laboratory, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, China.

Department of Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital, Boston, MA, United States.

出版信息

Front Mol Neurosci. 2024 May 22;17:1342233. doi: 10.3389/fnmol.2024.1342233. eCollection 2024.

DOI:10.3389/fnmol.2024.1342233
PMID:38840775
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11150584/
Abstract

INTRODUCTION

Disrupted in schizophrenia-1 (DISC1) is a scaffolding protein whose mutated form has been linked to schizophrenia, bipolar affective disorders, and recurrent major depression. DISC1 regulates multiple signaling pathways involved in neurite outgrowth and cortical development and binds directly to glycogen synthase kinase-3β (GSK-3β). Since ketamine activates GSK-3β, we examined the impact of ketamine on DISC1 and GSK-3β expression.

METHODS

Postnatal day 7 rat pups were treated with ketamine with and without the non-specific GSK-3β antagonist, lithium. Cleaved-caspase-3, GSK-3β and DISC1 levels were measured by immunoblots and DISC1 co-localization in neurons by immunofluorescence. Binding of DISC1 to GSK-3β was determined by co-immunoprecipitation. Neurite outgrowth was determined by measuring dendrite and axon length in primary neuronal cell cultures treated with ketamine and lithium.

RESULTS

Ketamine decreased DISC1 in a dose and time-dependent manner. This corresponded to decreases in phosphorylated GSK-3β, which implicates increased GSK-3β activity. Lithium significantly attenuated ketamine-induced decrease in DISC1 levels. Ketamine decreased co-immunoprecipitation of DISC1 with GSK-3β and axonal length.

CONCLUSION

These findings confirmed that acute administration of ketamine decreases in DISC1 levels and axonal growth. Lithium reversed this effect. This interaction provides a link between DISC1 and ketamine-induced neurodegeneration.

摘要

引言

精神分裂症相关基因1（DISC1）是一种支架蛋白，其突变形式与精神分裂症、双相情感障碍和复发性重度抑郁症有关。DISC1调节多个参与神经突生长和皮质发育的信号通路，并直接与糖原合酶激酶-3β（GSK-3β）结合。由于氯胺酮可激活GSK-3β，我们研究了氯胺酮对DISC1和GSK-3β表达的影响。

方法

对出生后第7天的大鼠幼崽用氯胺酮进行处理，同时使用或不使用非特异性GSK-3β拮抗剂锂盐。通过免疫印迹法检测裂解的半胱天冬酶-3、GSK-3β和DISC1的水平，并通过免疫荧光法检测神经元中DISC1的共定位。通过免疫共沉淀法确定DISC1与GSK-3β的结合。通过测量用氯胺酮和锂盐处理的原代神经元细胞培养物中树突和轴突的长度来确定神经突生长情况。

结果

氯胺酮以剂量和时间依赖性方式降低DISC1水平。这与磷酸化GSK-3β的减少相对应，这意味着GSK-3β活性增加。锂盐显著减弱了氯胺酮诱导的DISC1水平降低。氯胺酮减少了DISC1与GSK-3β的免疫共沉淀以及轴突长度。

结论

这些发现证实，急性给予氯胺酮会降低DISC1水平和轴突生长。锂盐可逆转这种效应。这种相互作用为DISC1与氯胺酮诱导的神经退行性变之间提供了联系。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f38e/11150584/e5c9cbc8f050/fnmol-17-1342233-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f38e/11150584/935706d92884/fnmol-17-1342233-g001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f38e/11150584/72f421f9fad7/fnmol-17-1342233-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f38e/11150584/e5c9cbc8f050/fnmol-17-1342233-g007.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f38e/11150584/72f421f9fad7/fnmol-17-1342233-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f38e/11150584/e5c9cbc8f050/fnmol-17-1342233-g007.jpg

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