Department of Neuropharmacology, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Yamanashi 409-3898, Japan.
GLIA Center, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Yamanashi 409-3898, Japan.
Int J Mol Sci. 2021 Dec 23;23(1):149. doi: 10.3390/ijms23010149.
In pathological brain conditions, glial cells become reactive and show a variety of responses. We examined Ca signals in pathological brains and found that reactive astrocytes share abnormal Ca signals, even in different types of diseases. In a neuropathic pain model, astrocytes in the primary sensory cortex became reactive and showed frequent Ca signals, resulting in the production of synaptogenic molecules, which led to misconnections of tactile and pain networks in the sensory cortex, thus causing neuropathic pain. In an epileptogenic model, hippocampal astrocytes also became reactive and showed frequent Ca signals. In an Alexander disease (AxD) model, -R239H knock-in mice showed accumulation of Rosenthal fibers, a typical pathological marker of AxD, and excessively large Ca signals. Because the abnormal astrocytic Ca signals observed in the above three disease models are dependent on type II inositol 1,4,5-trisphosphate receptors (IPRII), we reanalyzed these pathological events using IPRII-deficient mice and found that all abnormal Ca signals and pathologies were markedly reduced. These findings indicate that abnormal Ca signaling is not only a consequence but may also be greatly involved in the cause of these diseases. Abnormal Ca signals in reactive astrocytes may represent an underlying pathology common to multiple diseases.
在病理性大脑状态下，神经胶质细胞会发生反应，并表现出多种反应。我们检查了病理性大脑中的钙信号，发现反应性星形胶质细胞共享异常的钙信号，即使在不同类型的疾病中也是如此。在神经病理性疼痛模型中，初级感觉皮层中的星形胶质细胞变得活跃并表现出频繁的钙信号，导致突触生成分子的产生，这导致感觉皮层中触觉和疼痛网络的错误连接，从而导致神经病理性疼痛。在癫痫发病模型中，海马星形胶质细胞也变得活跃并表现出频繁的钙信号。在亚历山大病（AxD）模型中，R239H 敲入小鼠显示出 Rosenthal 纤维的积累，这是 AxD 的典型病理标志物，以及过度大的钙信号。由于在上述三种疾病模型中观察到的异常星形胶质细胞钙信号依赖于 II 型肌醇 1,4,5-三磷酸受体（IPRII），因此我们使用 IPRII 缺陷型小鼠重新分析了这些病理事件，发现所有异常钙信号和病理都明显减少。这些发现表明，异常钙信号不仅是后果，而且可能在很大程度上参与了这些疾病的原因。反应性星形胶质细胞中的异常钙信号可能代表多种疾病共有的潜在病理学。
