Department of Neuropsychiatry, Division of Neuroscience, Graduate School of Medicine, Mie University, Tsu 514-8507, Japan.
Int J Mol Sci. 2021 May 25;22(11):5623. doi: 10.3390/ijms22115623.
Recently, accumulating preclinical findings suggest the possibility that functional abnormalities of tripartite synaptic transmission play important roles in the pathophysiology of schizophrenia and affective disorder. Therefore, to explore the novel mechanisms of mood-stabilizing effects associated with tripartite synaptic transmission, the present study determined the effects of mood-stabilizing antipsychotics, clozapine (CLZ), quetiapine (QTP) and brexpiprazole (BPZ), on the astroglial l-glutamate release and expression of connexin43 (Cx43) in the astroglial plasma membrane using cortical primary cultured astrocytes. Neither acute (for 120 min) nor subchronic (for 7 days) administrations of CLZ, QTP and BPZ affected basal astroglial l-glutamate release, whereas both acute and subchronic administration of CLZ, QTP and BPZ concentration-dependently enhanced astroglial l-glutamate release through activated hemichannels. Subchronic administration of therapeutic-relevant concentration of valproate (VPA), a histone deacetylase inhibiting mood-stabilizing antiepileptic drug, enhanced the stimulatory effects of therapeutic-relevant concentration of CLZ, QTP and BPZ on astroglial l-glutamate release through activated hemichannel. Subchronic administration of therapeutic-relevant concentration of CLZ, QTP and BPZ did not affect Cx43 protein expression in the plasma membrane during resting stage. After subchronic administration of VPA, acute and subchronic administration of therapeutic-relevant concentrations of CLZ increased Cx43 protein expression in the plasma membrane. Both acute administrations of therapeutic-relevant concentrations of QTP and BPZ did not affect, but subchronic administrations enhanced Cx43 protein expression in the astroglial plasma membrane. Furthermore, protein kinase B (Akt) inhibitor suppressed the stimulatory effects of CLZ and QTP, but did not affect Cx43 protein expression in the astroglial plasma membrane. These results suggest that three mood-stabilizing atypical antipsychotics, CLZ, QTP and BPZ enhance tripartite synaptic glutamatergic transmission due to enhancement of astroglial Cx43 containing hemichannel activities; however, the Cx43 activating mechanisms of these three mood-stabilizing antipsychotics were not identical. The enhanced astroglial glutamatergic transmission induced by CLZ, QTP and BPZ is, at least partially, involved in the actions of these three mood-stabilizing antipsychotics.
最近，越来越多的临床前研究结果表明，三分突触传递的功能异常可能在精神分裂症和情感障碍的病理生理学中起重要作用。因此，为了探索与三分突触传递相关的新型稳定情绪作用机制，本研究使用皮质原代培养星形胶质细胞确定了稳定情绪的抗精神病药氯氮平（CLZ）、喹硫平（QTP）和布瑞哌唑（BPZ）对星形胶质细胞 l-谷氨酸释放和连接蛋白 43（Cx43）在星形胶质细胞质膜表达的影响。CLZ、QTP 和 BPZ 的急性（120 分钟）和亚慢性（7 天）给药均不影响基础星形胶质细胞 l-谷氨酸释放，而 CLZ、QTP 和 BPZ 的急性和亚慢性给药均浓度依赖性地通过激活半通道增强星形胶质细胞 l-谷氨酸释放。亚慢性给予治疗相关浓度的丙戊酸钠（VPA），一种组蛋白去乙酰化酶抑制性稳定情绪抗癫痫药物，通过激活半通道增强了治疗相关浓度的 CLZ、QTP 和 BPZ 对星形胶质细胞 l-谷氨酸释放的刺激作用。亚慢性给予治疗相关浓度的 CLZ、QTP 和 BPZ 不影响静息状态下半通道激活时质膜中的 Cx43 蛋白表达。给予 VPA 后，亚慢性给予治疗相关浓度的 CLZ 可增加质膜中 Cx43 蛋白表达，急性和亚慢性给予治疗相关浓度的 QTP 和 BPZ 均不影响质膜中 Cx43 蛋白表达，但亚慢性给予可增强质膜中 Cx43 蛋白表达。此外，蛋白激酶 B（Akt）抑制剂抑制了 CLZ 和 QTP 的刺激作用，但不影响星形胶质细胞质膜中的 Cx43 蛋白表达。这些结果表明，三种稳定情绪的非典型抗精神病药 CLZ、QTP 和 BPZ 通过增强星形胶质细胞 Cx43 含量的半通道活性增强三分突触谷氨酸能传递；然而，这三种稳定情绪的抗精神病药的 Cx43 激活机制并不相同。CLZ、QTP 和 BPZ 诱导的星形胶质细胞谷氨酸能传递增强至少部分涉及这三种稳定情绪的抗精神病药的作用。
