Department of Psychiatry, Osaka Medical College, Takatsuki, Japan.
Department of Psychiatry, Kobe University Graduate School of Medicine, Kobe, Japan.
Psychiatry Clin Neurosci. 2020 May;74(5):311-317. doi: 10.1111/pcn.12986. Epub 2020 Mar 5.
Electroconvulsive therapy (ECT) is effective for psychiatric disorders. However, its action mechanism remains unclear. We previously reported that transcription factor 7 (TCF7) was increased in patients successfully treated with ECT. TCF7 regulates Wnt pathway, which regulates adult hippocampal neurogenesis. Adult hippocampal neurogenesis is involved in the pathophysiology of psychiatric disorders. Astrocytes play a role in adult hippocampal neurogenesis via neurogenic factors. Of astrocyte-derived neurogenic factors, leukemia inhibitory factor (LIF) and fibroblast growth factor 2 (FGF2) activate Wnt pathway. In addition, adenosine triphosphate (ATP), released from excited neurons, activates astrocytes. Therefore, we hypothesized that ECT might increase LIF and/or FGF2 in astrocytes. To test this, we investigated the effects of ATP and electric stimulation (ES) on LIF and FGF2 expressions in astrocytes.
Astrocytes were derived from neonatal mouse forebrain and administered ATP and ES. The mRNA expression was estimated with quantitative reverse-transcription polymerase chain reaction. Protein concentration was measured with ELISA.
ATP increased LIF, but not FGF2, expression. Multiple ES, but not single, increased LIF expression. Knockdown of P2X2 receptor (P2X2R) attenuated ATP-induced increase of LIF mRNA expression. In contrast, P2X3 and P2X4 receptors intensified it.
P2X2R may mediate ATP-induced LIF expression in astrocytes and multiple ES directly increases LIF expression in astrocytes. Therefore, both ATP/P2X2R and multiple ES-induced increases of LIF expression in astrocytes might mediate the efficacy of ECT on psychiatric disorders. Elucidating detailed mechanisms of ATP/P2X2R and multiple ES-induced LIF expression is expected to result in the identification of new therapeutic targets for psychiatric disorders.
电抽搐治疗（ECT）对精神疾病有效。然而，其作用机制尚不清楚。我们之前的研究报道，成功接受 ECT 治疗的患者的转录因子 7（TCF7）增加。TCF7 调节 Wnt 通路，该通路调节成年海马神经发生。成年海马神经发生与精神疾病的病理生理学有关。星形胶质细胞通过神经发生因子在成年海马神经发生中起作用。在星形胶质细胞衍生的神经发生因子中，白血病抑制因子（LIF）和成纤维细胞生长因子 2（FGF2）激活 Wnt 通路。此外，兴奋神经元释放的三磷酸腺苷（ATP）激活星形胶质细胞。因此，我们假设 ECT 可能会增加星形胶质细胞中的 LIF 和/或 FGF2。为了验证这一点，我们研究了 ATP 和电刺激（ES）对星形胶质细胞中 LIF 和 FGF2 表达的影响。
从小鼠前脑分离星形胶质细胞，并给予 ATP 和 ES。用定量逆转录聚合酶链反应估计 mRNA 表达。用 ELISA 测量蛋白质浓度。
ATP 增加了 LIF，但不增加 FGF2 的表达。多次 ES，而不是单次 ES，增加了 LIF 的表达。P2X2 受体（P2X2R）的敲低减弱了 ATP 诱导的 LIF mRNA 表达的增加。相反，P2X3 和 P2X4 受体则加剧了这一过程。
P2X2R 可能介导 ATP 诱导的星形胶质细胞中 LIF 的表达，而多次 ES 直接增加星形胶质细胞中 LIF 的表达。因此，ATP/P2X2R 和多次 ES 诱导的星形胶质细胞中 LIF 表达的增加可能介导 ECT 对精神疾病的疗效。阐明 ATP/P2X2R 和多次 ES 诱导的 LIF 表达的详细机制有望为精神疾病的治疗确定新的靶点。
