Montreal Neurological Institute, Department of Neurology & Neurosurgery, McGill University, Montréal, Quebec, Canada.
Montreal Neurological Institute, Department of Neurology & Neurosurgery, McGill University, Montréal, Quebec, Canada.
EBioMedicine. 2024 Jun;104:105161. doi: 10.1016/j.ebiom.2024.105161. Epub 2024 May 20.
Bipolar disorder (BD) is a multifactorial psychiatric illness affecting ∼1% of the global adult population. Lithium (Li), is the most effective mood stabilizer for BD but works only for a subset of patients and its mechanism of action remains largely elusive.
In the present study, we used iPSC-derived neurons from patients with BD who are responsive (LR) or not (LNR) to lithium. Combined electrophysiology, calcium imaging, biochemistry, transcriptomics, and phosphoproteomics were employed to provide mechanistic insights into neuronal hyperactivity in BD, investigate Li's mode of action, and identify alternative treatment strategies.
We show a selective rescue of the neuronal hyperactivity phenotype by Li in LR neurons, correlated with changes to Na conductance. Whole transcriptome sequencing in BD neurons revealed altered gene expression pathways related to glutamate transmission, alterations in cell signalling and ion transport/channel activity. We found altered Akt signalling as a potential therapeutic effect of Li in LR neurons from patients with BD, and that Akt activation mimics Li effect in LR neurons. Furthermore, the increased neural network activity observed in both LR & LNR neurons from patients with BD were reversed by AMP-activated protein kinase (AMPK) activation.
These results suggest potential for new treatment strategies in BD, such as Akt activators in LR cases, and the use of AMPK activators for LNR patients with BD.
Supported by funding from ERA PerMed, Bell Brain Canada Mental Research Program and Brain & Behavior Research Foundation.
双相情感障碍（BD）是一种影响全球成年人口约 1%的多因素精神疾病。锂（Li）是最有效的心境稳定剂，用于治疗 BD，但仅对一部分患者有效，其作用机制仍很大程度上难以捉摸。
在本研究中，我们使用对锂有反应（LR）或无反应（LNR）的 BD 患者的 iPSC 衍生神经元。联合电生理学、钙成像、生物化学、转录组学和磷酸化蛋白质组学，为 BD 中神经元过度活跃提供机制见解，研究 Li 的作用机制，并确定替代治疗策略。
我们表明 Li 选择性地挽救了 LR 神经元中的神经元过度活跃表型，与 Na 电导变化相关。BD 神经元的全转录组测序显示，与谷氨酸传递、细胞信号转导和离子转运/通道活性改变相关的基因表达途径发生改变。我们发现 Akt 信号转导是 Li 在 BD 患者 LR 神经元中的潜在治疗作用，并且 Akt 激活模拟了 Li 在 LR 神经元中的作用。此外，在 BD 患者的 LR 和 LNR 神经元中观察到的增加的神经网络活性可通过 AMP 激活蛋白激酶（AMPK）激活逆转。
这些结果表明，在 BD 中可能存在新的治疗策略，例如在 LR 病例中使用 Akt 激活剂，以及在 LNR 患者中使用 AMPK 激活剂。
得到 ERA PerMed、Bell Brain Canada Mental Research Program 和 Brain & Behavior Research Foundation 的资助。
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