The role of astrocytes in brain plasticity has not been extensively studied compared with that of neurons. Here we adopted integrative translational and reverse-translational approaches to explore the role of an astrocyte-specific major water channel in the brain, aquaporin-4 (AQP4), in brain plasticity and learning. We initially identified the most prevalent genetic variant of AQP4 (single nucleotide polymorphism of rs162008 with C or T variation, which has a minor allele frequency of 0.21) from a human database (n=60 706) and examined its functionality in modulating the expression level of AQP4 in an in vitro luciferase reporter assay. In the following experiments, AQP4 knock-down in mice not only impaired hippocampal volumetric plasticity after exposure to enriched environment but also caused loss of long-term potentiation after theta-burst stimulation. In humans, there was a cross-sectional association of rs162008 with gray matter (GM) volume variation in cortices, including the vicinity of the Perisylvian heteromodal language area (Sample 1, n=650). GM volume variation in these brain regions was positively associated with the semantic verbal fluency. In a prospective follow-up study (Sample 2, n=45), the effects of an intensive 5-week foreign language (English) learning experience on regional GM volume increase were modulated by this AQP4 variant, which was also associated with verbal learning capacity change. We then delineated in mice mechanisms that included AQP4-dependent transient astrocytic volume changes and astrocytic structural elaboration. We believe our study provides the first integrative evidence for a gliogenetic basis that involves AQP4, underlying language-associated brain plasticity.

中文翻译：

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星形细胞水通道aquaporin-4调节小鼠和人类的大脑可塑性：与语言相关的学习的潜在胶质生成机制。

与神经元相比，尚未广泛研究星形胶质细胞在大脑可塑性中的作用。在这里，我们采用整合翻译和反向翻译方法来探索星形胶质细胞特定的主要水通道在大脑中的水通道蛋白4（AQP4）在大脑可塑性和学习中的作用。我们最初从人类数据库（n = 60 706）中确定了AQP4最普遍的遗传变异（具有C或T变异的rs162008的单核苷酸多态性，其次等位基因频率为0.21），并研究了其在调节表达水平中的功能萤光素酶报告基因检测中AQP4的含量 在以下实验中，小鼠AQP4敲低不仅损害了其在丰富环境下的海马体积可塑性，而且在theta-burst刺激后导致了长期增强能力的丧失。在人类中，rs162008与皮质中的灰质（GM）体积变化（包括Perisylvian异质语言区域附近）之间存在横断面关联（示例1，n = 650）。这些大脑区域的GM量变化与语义语言流利度呈正相关。在一项前瞻性随访研究中（样本2，n = 45），这种AQP4变体调节了为期5周的强化外语（英语）学习经验对区域GM量增加的影响，这也与口头学习有关容量变化。然后，我们在小鼠中描述了包括AQP4依赖性瞬时星形细胞体积变化和星形细胞结构精细化的机制。我们相信我们的研究为涉及AQP4（与语言相关的大脑可塑性的潜在基础）的成胶基础提供了第一个综合证据。