Heterogeneity in astrocyte sodium signalling: Functional consequences

早期在幼年小鼠海马区和小脑进行的工作已经证实，星形胶质细胞对兴奋性突触活动的反应是短暂的钠浓度增加，这主要是由高亲和力谷氨酸摄取产生的。星形胶质细胞钠的变化在功能上具有很高的相关性，因为它们改变了钠依赖的转运体的活性，如钠/钙交换(NCX)，并在神经代谢偶联中发挥重要作用。在SPP的第一个资助期，我们揭示了小鼠脑内星形胶质细胞钠信号存在发育、亚细胞和区域间的异质性。在此背景下，我们发现在新皮质和海马区CA1区钠信号的大小和通路存在显著差异。皮质星形胶质细胞不仅对谷氨酸和谷氨酸能传入的激活有更大的钠瞬变反应，而且还经历了强大的NMDA受体介导的钠内流，这是海马星形胶质细胞所缺乏的成分。在第二个资助期，我们现在的目标是解决这种异质性可能产生的功能后果。利用高分辨率、基于荧光的离子瞬变成像，结合全细胞膜片钳和针对代谢物的基因编码纳米传感器，我们将检验这样一种假设，即活动诱导的星形胶质细胞钠瞬变通过NCX与细胞内钙稳态和信号耦合。此外，我们认为它们直接影响神经胶质细胞的代谢。海马区和大脑皮层之间与活动相关的星形胶质细胞钠信号的大小的显著差异表明这两个大脑区域的功能不同。我们推测，星形胶质细胞的这种区域间功能异质性主要与通过NMDA受体的钠内流的异质性有关。最后，我们认为，与海马网相比，差异钠信号-由NMDA受体介导-放大了与钠相关的钙信号，并增强了新皮质中的神经代谢耦合。

Earlier work performed in juvenile mouse hippocampus and cerebellum has established that astrocytes respond to excitatory synaptic activity with transient increases in their sodium concentration, which are mainly generated by high-affinity glutamate uptake. Changes in astrocyte sodium are functionally highly relevant because they alter the activity of sodium-dependent transporters such as the sodium/calcium exchanger (NCX) and serve an important role in neuro-metabolic coupling. In the first funding period of the SPP, we revealed the existence of developmental, subcellular and inter-regional heterogeneity in astrocyte sodium signalling in the mouse brain. In this context, we uncovered marked differences in the magnitude and pathways of sodium signals between neocortex and hippocampal CA1 region. Cortical astrocytes not only respond with much larger sodium transients to glutamate and to activation of glutamatergic afferents, they also experience strong NMDA-receptor-mediated sodium influx, a component, which hippocampal astrocytes lack. In the second funding period, we now aim to address the possible functional consequences of this heterogeneity. Employing high-resolution, fluorescence-based imaging of ion transients in combination with whole-cell patch-clamp and genetically-encoded nanosensors for metabolites, we will test the hypothesis that activity-induced astrocyte sodium transients are coupled to intracellular calcium homeostasis and signalling through NCX. Furthermore, we propose that they directly influence glial metabolism. The striking difference in the magnitude of activity-related astrocyte sodium signals between hippocampus and neocortex suggests functional differences between both brain regions. We hypothesize that this inter-regional functional heterogeneity of astrocytes mainly relates to the heterogeneity in sodium influx through NMDA receptors. Finally, we propose that differential sodium signalling -as mediated by NMDA receptors- amplifies sodium-related calcium signalling and augments neuro-metabolic coupling in neocortical as compared to hippocampal networks.