HDAC1/2/3‐mediated downregulation of neurogranin is involved in cognitive impairment in offspring exposed to maternal subclinical hypothyroidism

后代 神经颗粒素 亚临床感染 内分泌学 海马体 内科学 突触可塑性 怀孕 胎儿 医学 心理学 生物 信号转导 遗传学 蛋白激酶C 受体
作者
Xi Yu,Jun Guo,Yueyang Song,Bin Wei,Yajun Shi,艳 赵,Zejun Zhao,Qinqin Gao,Bin Wang,Miao Sun
出处
期刊:The FASEB Journal [Wiley]
卷期号:38 (12)
标识
DOI:10.1096/fj.202400389r
摘要

Abstract Subclinical hypothyroidism (SCH) in pregnancy is the most common form of thyroid dysfunction in pregnancy, which can affect fetal nervous system development and increase the risk of neurodevelopmental disorders after birth. However, the mechanism of the effect of maternal subclinical hypothyroidism on fetal brain development and behavioral phenotypes is still unclear and requires further study. In this study, we constructed a mouse model of maternal subclinical hypothyroidism by exposing dams to drinking water containing 50 ppm propylthiouracil (PTU) during pregnancy and found that its offspring were accompanied by severe cognitive deficits by behavioral testing. Mechanistically, gestational SCH resulted in the upregulation of protein expression and activity of HDAC1/2/3 in the hippocampus of the offspring. ChIP analysis revealed that H3K9ac on the neurogranin (Ng) promoter was reduced in the hippocampus of the offspring of SCH, with a significant reduction in Ng protein, leading to reduced expression levels of synaptic plasticity markers PSD95 (a membrane‐associated protein in the postsynaptic density) and SYN (synaptophysin, a specific marker for presynaptic terminals), and impaired synaptic plasticity. In addition, administration of MS‐275 (an HDAC1/2/3‐specific inhibitor) to SCH offspring alleviated impaired synaptic plasticity and cognitive dysfunction in offspring. Thus, our study suggests that maternal subclinical hypothyroidism may mediate offspring cognitive dysfunction through the HDAC1/2/3‐H3K9ac‐Ng pathway. Our study contributes to the understanding of the signaling mechanisms underlying maternal subclinical hypothyroidism‐mediated cognitive impairment in the offspring.
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