From the Montreal Neurological Institute, Department of Neurology & Neurosurgery, McGill University, Montréal, Que., Canada (Khayachi, Ase, Liao, Kamesh, Kuhlmann, Dion, Séguéla Rouleau, Milnerwood); the Department of Human Genetics, McGill University, Montréal, Que., Canada (Rouleau); McGill University Health Centre Research Institute, Montréal, Que., Canada (Schorova); the Université de Paris, Institut de Psychiatrie et Neuroscience of Paris (IPNP), INSERM U1266, GHU Paris Psychiatrie et Neurosciences, Paris, France (Chaumette); the Department of Psychiatry, McGill University, Montréal Que., Canada (Chaumette); and the Department of Psychiatry, Dalhousie University, Halifax, NS, Canada (Alda).
J Psychiatry Neurosci. 2021 Jun 2;46(3):E402-E414. doi: 10.1503/jpn.200185.
Bipolar disorder is characterized by cyclical alternation between mania and depression, often comorbid with psychosis and suicide. Compared with other medications, the mood stabilizer lithium is the most effective treatment for the prevention of manic and depressive episodes. However, the pathophysiology of bipolar disorder and lithium’s mode of action are yet to be fully understood. Evidence suggests a change in the balance of excitatory and inhibitory activity, favouring excitation in bipolar disorder. In the present study, we sought to establish a holistic understanding of the neuronal consequences of lithium exposure in mouse cortical neurons, and to identify underlying mechanisms of action.
We used a range of technical approaches to determine the effects of acute and chronic lithium treatment on mature mouse cortical neurons. We combined RNA screening and biochemical and electrophysiological approaches with confocal immunofluorescence and live-cell calcium imaging.
We found that only chronic lithium treatment significantly reduced intracellular calcium flux, specifically by activating metabotropic glutamatergic receptor 5. This was associated with altered phosphorylation of protein kinase C and glycogen synthase kinase 3, reduced neuronal excitability and several alterations to synapse function. Consequently, lithium treatment shifts the excitatory–inhibitory balance toward inhibition.
The mechanisms we identified should be validated in future by similar experiments in whole animals and human neurons.
Together, the results revealed how lithium dampens neuronal excitability and the activity of the glutamatergic network, both of which are predicted to be overactive in the manic phase of bipolar disorder. Our working model of lithium action enables the development of targeted strategies to restore the balance of overactive networks, mimicking the therapeutic benefits of lithium but with reduced toxicity.
双相情感障碍的特征是躁狂和抑郁的周期性交替，常伴有精神病和自杀。与其他药物相比，心境稳定剂锂是预防躁狂和抑郁发作最有效的治疗方法。然而，双相情感障碍的病理生理学和锂的作用方式尚未完全了解。有证据表明，兴奋和抑制活动的平衡发生了变化，双相情感障碍中更偏向于兴奋。在本研究中，我们试图全面了解锂暴露对成熟小鼠皮质神经元的神经后果，并确定潜在的作用机制。
我们使用了一系列技术方法来确定急性和慢性锂处理对成熟小鼠皮质神经元的影响。我们将 RNA 筛选、生化和电生理方法与共聚焦免疫荧光和活细胞钙成像相结合。
我们发现只有慢性锂处理才能显著降低细胞内钙通量，具体来说是通过激活代谢型谷氨酸受体 5 实现的。这与蛋白激酶 C 和糖原合酶激酶 3 的磷酸化改变、神经元兴奋性降低以及突触功能的几个改变有关。因此，锂处理将兴奋性-抑制性平衡向抑制性转变。
我们确定的机制应在未来通过在整体动物和人类神经元中进行类似的实验进行验证。
总的来说，这些结果揭示了锂如何抑制神经元兴奋性和谷氨酸能网络的活性，这两者在双相情感障碍的躁狂期都被预测为过度活跃。我们的锂作用工作模型使开发靶向策略成为可能，以恢复过度活跃网络的平衡，模拟锂的治疗益处，但毒性降低。
