Impaired learning and memory generated by hyperthyroidism is rescued by restoration of AMPA and NMDA receptors function
Impaired learning and memory generated by hyperthyroidism is rescued by restoration of AMPA and NMDA receptors function
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DOI：
10.1016/j.nbd.2022.105807
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发表时间：
2022-07-06
影响因子：
6.1
通讯作者：
Guo，Guoqing
中科院分区：
文献类型：
--
作者：
Zhu，Wei;Wu，Fengming;Guo，Guoqing
甲状腺机能亢进已被确定为认知障碍的危险因素。海马是大脑中与认知功能相关的关键区域，其中兴奋性突触传递在学习记忆过程中起着重要作用。然而，甲状腺机能亢进通过突触机制导致认知功能障碍的机制尚不清楚。我们在反复注射三碘甲状腺原氨酸（T3）的动物模型中研究了甲状腺功能亢进的突触机制。这些小鼠在新物体识别测试、y形迷宫测试和莫里斯水迷宫测试中表现出学习和记忆受损，并且在高+迷宫中表现出焦虑升高。甲亢小鼠海马CA1区成熟树突棘明显减少，同时海马AMPA-和nmda型谷氨酸受体水平降低。在原代培养的海马神经元中，AMPA-和nmda型谷氨酸受体水平也下降，全细胞膜片钳记录显示，T3处理后兴奋性突触功能明显减弱。值得注意的是，通过腹腔注射AMPAR激动剂CX546或NMDAR激动剂NMDA来激活AMPAR或NMDAR，可以恢复兴奋性突触功能并纠正甲状腺功能亢进小鼠受损的学习和记忆缺陷。总之，我们的发现揭示了一种以前未被认识到的AMPAR和nmdar依赖机制，参与调节甲亢患者海马兴奋性突触传递和学习记忆障碍。
Hyperthyroidism has been identified as a risk factor for cognitive disorders. The hippocampus is a key brain region associated with cognitive function, among which excitatory synapse transmission plays an important role in the process of learning and memory. However, the mechanism by which hyperthyroidism leads to cognitive dysfunction through a synaptic mechanism remains unknown. We investigated the synaptic mechanisms in the effects of hyperthyroidism in an animal model that involved repeated injection of triiodothyronine (T3). These mice displayed impaired learning and memory in the Novel object recognition test, Y-maze test, and Morris Water Maze test, as well as elevated anxiety in the elevated plus maze. Mature dendritic spines in the hippocampal CA1 region of hyperthyroid mice were significantly decreased, accompanied by decreased level of AMPA- and NMDA-type glutamate receptors in the hippocampus. In primary cultured hippocampal neurons, levels of AMPA- and NMDA-type glutamate receptors also decreased and whole-cell patch-clamp recording revealed that excitatory synaptic function was obviously attenuated after T3 treatment. Notably, pharmacological activation of AMPAR or NMDAR by intraperitoneal injection of CX546, an AMPAR agonist, or NMDA, an NMDAR agonist can restore excitatory synaptic function and corrected impaired learning and memory deficit in hyperthyroid mice. Together, our findings uncovered a previously unrecognized AMPAR and NMDAR-dependent mechanism involved in regulating hippocampal excitatory synaptic transmission and learning and memory disorders in hyperthyroidism.