Department of Endocrinology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, 250021, China; Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China; Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, 250021, China; Shandong Institute of Endocrine and Metabolic Diseases, Jinan, Shandong, 250021, China.
Department of Endocrinology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, 250021, China; Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China; Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, 250021, China; Shandong Institute of Endocrine and Metabolic Diseases, Jinan, Shandong, 250021, China; Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing, 100005, China.
Biochem Biophys Res Commun. 2024 Apr 16;704:149723. doi: 10.1016/j.bbrc.2024.149723. Epub 2024 Feb 28.
Subclinical hyperthyroidism is defined biochemically as a low or undetectable thyroid-stimulating hormone (TSH) with normal thyroid hormone levels. Low TSHR signaling is considered to associate with cognitive impairment. However, the underlying molecular mechanism by which TSHR signaling modulates memory is poorly understood. In this study, we found that Tshr-deficient in the hippocampal neurons impairs the learning and memory abilities of mice, accompanying by a decline in the number of newborn neurons. Notably, Tshr ablation in the hippocampus decreases the expression of Wnt5a, thereby inactivating the β-catenin signaling pathway to reduce the neurogenesis. Conversely, activating of the Wnt/β-catenin pathway by the agonist SKL2001 results in an increase in hippocampal neurogenesis, resulting in the amelioration in the deficits of memory caused by Tshr deletion. Understanding how TSHR signaling in the hippocampus regulates memory provides insights into subclinical hyperthyroidism affecting cognitive function and will suggest ways to rationally design interventions for neurocognitive disorders.
亚临床甲状腺功能亢进症在生化上定义为甲状腺刺激激素（TSH）低或检测不到，而甲状腺激素水平正常。低 TSHR 信号被认为与认知障碍有关。然而，TSHR 信号调节记忆的潜在分子机制尚不清楚。在这项研究中，我们发现海马神经元中 Tshr 缺失会损害小鼠的学习和记忆能力，伴随着新生神经元数量的减少。值得注意的是，海马体中 Tshr 的缺失会降低 Wnt5a 的表达，从而使β-连环蛋白信号通路失活，减少神经发生。相反，激动剂 SKL2001 激活 Wnt/β-连环蛋白通路会导致海马神经发生增加，从而改善由 Tshr 删除引起的记忆缺陷。了解海马体中的 TSHR 信号如何调节记忆，可以深入了解亚临床甲状腺功能亢进症影响认知功能的机制，并为合理设计神经认知障碍干预措施提供思路。
