Calcium Signalling Among Non-Neuronal Brain Cells

在以前的研究中，我们已经报道了缝隙连接偶联的神经胶质细胞之间的钙波可能形成了体内扩散性抑制的细胞底物。最近，我们注意到在脑片星形胶质细胞中发起的钙波可以传播到脑内皮细胞和脑膜细胞；所有这些细胞类型都表达连接蛋白43，这可能允许它们通过同型缝隙连接相互异型合胞相互作用。在此基础上，我们提出了一种假设，即星形细胞钙波可能通过沿毛细血管传播以及通过星形细胞合体来侵袭大脑。这些实验将测试内皮细胞钙波可能跟随静脉内皮细胞侵入脑膜血管系统，从而招募脑膜细胞和三叉神经感觉传入。这种被提出的途径，通过绕过和穿越软脑膜的限制性屏障，将允许脑膜血管及其三叉神经感觉传入重新招募到扩散性抑郁的实质波中。我们在这里提出，这一情景可能会在操作上模拟成人偏头痛的开始。在平行实验中，我们还将跟进我们最近观察到的类固醇诱导的星形细胞钙信号增强，询问非神经元脑细胞类型之间的钙信号是否可能受到性腺类固醇的调节。特别是，我们试图确定周期性的女性激素雌激素和孕酮是否增强了星形胶质细胞到内皮细胞的信号，如果是的话，脑膜血管重新进入实质钙波的可能性是否因此增加。这一途径可能解释了偏头痛的大部分症状，而钙信号的类固醇强化可能解释了偏头痛发生的周期性。我们提出的远距离多细胞钙信号通路，以及伴随而来的激素调节，建议立即采取可测试的策略来消除它。

In previous studies, we have reported that calcium waves among gap junction-coupled glia may form the cellular substrate for spreading depression in vivo. Recently, we have noted that calcium waves initiated in astrocytes in slices can propagate to brain endothelial and meningeal cells; all of these cell types express connexin43, which may allow their mutual heterotypic syncytial interaction through homotypic gap junctions. On this basis, we propose to test the hypothesis that astrocytic calcium waves may thereby invade the brain by propagating along the capillary vasculature, as well as through the astrocytic syncytium. These experiments will test the possibility that endothelial calcium waves may follow the venular endothelium to invade the meningeal vasculature, thereby recruiting both meningeal cells and trigeminal sensory afferents. This proposed pathway, by bypassing and traversing the restrictive barrier of the pia limitans, would permit the recruitment of both the meningeal vasculature and its trigeminal sensory afferents into parenchymal waves of spreading depression. We propose here that this scenario might operationally model the initiation of migraine headache in adults. In parallel experiments, we will also follow-up our recent observation of a steroid-induced accentuation of astrocytic calcium signaling, by asking whether calcium signaling among non-neuronal brain cell types may be modulated by gonadal steroids. In particular, we seek to determine whether the cyclical female hormones estrogen and progesterone potentiate signaling from astrocytes to endothelial cells, and if so, whether the likelihood of meningovascular recruitment into a parenchymal calcium wave is thereby increased. This pathway might account for much of the symptomatology of migraine headache, while steroidal accentuation of calcium signaling might account for the cyclicity of migraine occurrence. The long-distance multicellular calcium signaling pathway that we propose, and its attendant hormonal regulation, suggests immediately testable strategies for its abrogation.