Congenital Hypothyroidism Dysregulates TRPC6 to Mediate Abnormal Dendritic Spine Growth of Hippocampal Neurons

IF 5 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics Pub Date : 2025-09-25 DOI:10.1111/cns.70618

Tianci Li, Feifei Shen, Lingling Li, Peng Chen, Zhiwen Zhu, Yuqin Zheng, Haiying Li, Guihai Suo, Yongjun Wang, Jinlong Shi, Youjia Wu

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Abstract

Background

Congenital hypothyroidism (CH) may lead to irreversible neurological dysfunction of offspring by affecting hippocampal morphogenesis. The dentate gyrus (DG) is primarily the affected tissue by the CH, in which the dendritic spine density of gyrus granule cells (DGCs) is significantly reduced, thereby resulting in the cognitive impairment. The CaMKIV/CREB signaling pathway has been shown to mediate the deficient growth of DGCs dendritic spines, but the mechanism of CH in modulating the Ca²⁺-dependent CaMKIV is still elusive.

Methods

CH model of rat pups was prepared by the supply of 0.02% methimazole in the drinking water of pregnant dams from the 9th day of gestation. The dendritic spine density of hippocampal DGCs was detected by Golgi staining before or after administration of drugs. Additionally, the expression of CH-mediated effectors in the hippocampus or primary neurons was determined by Western blot or RT-PCR, and the immunofluorescence or subcellular fractionation was used to examine the distribution of these factors.

Results

In the present study, the calcium influx-related channel TRPC6 was identified under the regulation of T3, which was significantly downregulated in the DGCs of CH pups. TRPC6 deficiency has been revealed to decrease the dendritic spine density by affecting intracellular calcium transients and the CaMKIV/CREB signaling pathway. Pharmacological activation of TRPC6 with hyperforin was shown to be efficient in the rescue of DGCs dendritic spines and in improving the cognitive function of CH pups.

Conclusions

CH of the neonates leads to downregulation of TRPC6 in hippocampal dentate gyrus neurons, which affects calcium influx and decreases activation of CaMKIV and downstream signaling, thereby causing abnormal growth of DGCs' dendritic spines and impaired cognitive function in the offspring. This study provides a new target for CH-mediated developmental abnormality of the hippocampus in the offspring.

Abstract Image

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先天性甲状腺功能减退症异常调节TRPC6介导海马神经元异常树突棘生长。

背景：先天性甲状腺功能减退症（CH）可能通过影响海马形态发生导致后代不可逆的神经功能障碍。齿状回（DG）是CH的主要影响组织，其中齿状回颗粒细胞（DGCs）的树突棘密度显著降低，从而导致认知障碍。CaMKIV/CREB信号通路已被证明介导DGCs树突棘生长缺陷，但CH调节Ca2+依赖性CaMKIV的机制仍不清楚。方法：从妊娠第9天开始，在孕鼠饮水中添加0.02%甲巯咪唑制备大鼠幼鼠CH模型。用高尔基染色法检测给药前后海马DGCs的树突棘密度。此外，采用Western blot或RT-PCR检测海马或原代神经元中ch介导的效应物的表达，并采用免疫荧光或亚细胞分离检测这些因子的分布。结果：本研究发现T3调控下钙流入相关通道TRPC6在CH幼崽DGCs中显著下调。TRPC6缺乏可通过影响细胞内钙瞬变和CaMKIV/CREB信号通路降低树突棘密度。用hyperperin激活TRPC6可以有效地挽救DGCs树突棘，并改善CH幼鼠的认知功能。结论：新生儿CH可导致海马齿状回神经元TRPC6下调，影响钙内流，降低CaMKIV及下游信号的激活，从而导致后代DGCs树突棘生长异常，认知功能受损。本研究为ch介导的后代海马发育异常提供了新的靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

CNS Neuroscience & Therapeutics 医学-神经科学

CiteScore

7.30

自引率

12.70%

发文量

240

审稿时长

2 months

期刊介绍： CNS Neuroscience & Therapeutics provides a medium for rapid publication of original clinical, experimental, and translational research papers, timely reviews and reports of novel findings of therapeutic relevance to the central nervous system, as well as papers related to clinical pharmacology, drug development and novel methodologies for drug evaluation. The journal focuses on neurological and psychiatric diseases such as stroke, Parkinson’s disease, Alzheimer’s disease, depression, schizophrenia, epilepsy, and drug abuse.