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Maternal Subclinical Hypothyroidism Impairs Neurodevelopment in Rat Offspring by Inhibiting the CREB Signaling Pathway

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Abstract

Thyroid hormone is indispensable for fetal brain development, and maternal thyroid hormone deficiency is thought to result in severe and irreversible brain impairments in learning and memory. Epidemiological and animal studies by our group had shown that maternal subclinical hypothyroidism had significant negative impact on neurodevelopment. But, the underlying mechanisms responsible for these neurological alterations remain unclear. In the present study, we performed thyroidectomy and injected L-T4 daily in Wistar rats to induce maternal subclinical hypothyroidism. Our data indicated that the pups from subclinical group showed prolonged latencies during the learning process in the Morris water maze as compared to the control group. Transcription factor cAMP response element-binding protein (CREB) signaling pathway is closely associated with synaptic plasticity, learning, and memory. Consistent with behavioral results, Western blotting also showed decreased activation of three important upstream modulators of CREB signaling pathway: phospho-mitogen-activated protein kinases (P-ERK1/2), phospho-calcium-dependent-calmodulin kinase IV (P-CaMKIV), phospho-serine/threonine protein kinase AKT(P-AKT), as well as total CREB and phospho-CREB as compared to the control at postnatal day 7 (PND 7) in hippocampus. Our findings suggested that decreased activation of the CREB signaling pathway in pups was related to impairments of cognitive function caused by maternal subclinical hypothyroidism.

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Acknowledgments

This work was supported by the 973 Science and Technology Research Foundation, Ministry of Science and Technology in China (Grant 2011CB512112); the Chinese National Natural Science Foundation (Grant 81170730, 30971400); and Program for Liaoning Excellent Talents in University (Grant LR2011022).

Conflict of Interest

The authors declares that there are no conflicts of interest.

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Authors and Affiliations

  1. Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Affiliated Hospital of China Medial University, No.155 Nanjing North Street, Shenyang, 110001, People’s Republic of China

    Yuanyuan Zhang, Yuxin Fan, Xiaohui Yu, Xinyi Wang, Suqing Bao, Jiashu Li, Chenling Fan, Zhongyan Shan & Weiping Teng

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  1. Yuanyuan Zhang
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Correspondence to Zhongyan Shan or Weiping Teng.

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Zhang, Y., Fan, Y., Yu, X. et al. Maternal Subclinical Hypothyroidism Impairs Neurodevelopment in Rat Offspring by Inhibiting the CREB Signaling Pathway. Mol Neurobiol 52, 432–441 (2015). https://doi.org/10.1007/s12035-014-8855-x

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  • DOI: https://doi.org/10.1007/s12035-014-8855-x

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