Background: The mechanisms underlying the action of lithium (LiCl) in bipolar disorder(BD) are still far from being completely understood. Previous evidence has revealed that BD is characterized by glutamate hyperexcitability, suggesting that LiCl may act, at least partially, by toning down glutamatergic signaling abnormalities. Objective: In this study, taking advantage of western blot and confocal microscopy, we used a combination of integrative molecular and morphological approaches in rats exposed to repeated administration of LiCl at a therapeutic dose (between 0.6 and 1.2 mmol/l) and sacrificed at two different time points, i.e., 24 hours and 7 days after the last exposure. Results: We report that repeated LiCl treatment activates multiple, parallel, but also converging forms of compensatory neuroplasticity related to glutamatergic signaling. More specifically, LiCl promoted a wave of neuroplasticity in the hippocampus, involving the synaptic recruitment of GluN2A-containing NMDA receptors, GluA1-containing AMPA receptors, and the neurotrophin BDNF that are indicative of a more plastic spine. The latter is evidenced by morphological analyses showing changes in dendritic spine morphology, such as increased length and head diameter of such spines. These changes may counteract the potentially negative extra-synaptic movements of GluN2B-containing NMDA receptors as well as the increase in the formation of GluA2-lacking Ca2+-permeable AMPA receptors. Conclusion: Our findings highlight a previously unknown cohesive picture of the glutamatergic implications of LiCl action that persist long after the end of its administration, revealing for the first time a profound and persistent reorganization of the glutamatergic postsynaptic density receptor composition and structure.

中文翻译：

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长期锂治疗改变大鼠海马的 NMDA 和 AMPA 受体突触可用性和树突棘组织

背景：锂 (LiCl) 在双相情感障碍 (BD) 中的作用机制仍远未完全了解。先前的证据表明，BD 的特点是谷氨酸过度兴奋，这表明 LiCl 可能至少部分通过减弱谷氨酸信号异常来发挥作用。目的：在本研究中，利用蛋白质印迹和共聚焦显微镜，我们对重复给予治疗剂量（0.6 至 1.2 mmol/l）LiCl 的大鼠采用综合分子和形态学方法，并在 2 小时处死。不同的时间点，即最后一次暴露后的24小时和7天。结果：我们报告重复的 LiCl 治疗激活了与谷氨酸能信号传导相关的多种、平行且会聚形式的代偿性神经可塑性。更具体地说，LiCl促进了海马体的神经可塑性浪潮，涉及含有GluN2A的NMDA受体、含有GluA1的AMPA受体和神经营养蛋白BDNF的突触募集，这表明脊柱更具可塑性。后者通过形态分析证明了树突棘形态的变化，例如树突棘的长度和头部直径的增加。这些变化可能抵消含有 GluN2B 的 NMDA 受体潜在的负面突触外运动，以及缺乏 GluA2 的 Ca2+ 渗透性 AMPA 受体形成的增加。结论：我们的研究结果强调了以前未知的关于氯化锂作用的谷氨酸能影响的连贯图景，这种影响在其给药结束后仍持续很长时间，首次揭示了谷氨酸能突触后密度受体组成和结构的深刻而持久的重组。