State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, IDG/McGovern Institute for Brain Research, Beijing Frontier Research Center for Biological Structure, Beijing Advanced Innovation Center for Structural Biology, School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China.
State Key Laboratory of Membrane Biology, Peking-Tsinghua Center for Life Sciences, PKU-IDG/McGovern Institute for Brain Research, College of Future Technology, Peking University, Beijing 100871, China.
Neuron. 2022 Sep 21;110(18):2984-2999.e8. doi: 10.1016/j.neuron.2022.07.010. Epub 2022 Aug 12.
Adult brain activities are generally believed to be dominated by chemical and electrical transduction mechanisms. However, the importance of mechanotransduction mediated by mechano-gated ion channels in brain functions is less appreciated. Here, we show that the mechano-gated Piezo1 channel is expressed in the exploratory processes of astrocytes and utilizes its mechanosensitivity to mediate mechanically evoked Ca responses and ATP release, establishing Piezo1-mediated mechano-chemo transduction in astrocytes. Piezo1 deletion in astrocytes causes a striking reduction of hippocampal volume and brain weight and severely impaired (but ATP-rescuable) adult neurogenesis in vivo, and it abolishes ATP-dependent potentiation of neural stem cell (NSC) proliferation in vitro. Piezo1-deficient mice show impaired hippocampal long-term potentiation (LTP) and learning and memory behaviors. By contrast, overexpression of Piezo1 in astrocytes sufficiently enhances mechanotransduction, LTP, and learning and memory performance. Thus, astrocytes utilize Piezo1-mediated mechanotransduction mechanisms to robustly regulate adult neurogenesis and cognitive functions, conceptually highlighting the importance of mechanotransduction in brain structure and function.
成人的大脑活动通常被认为主要由化学和电转导机制主导。然而，机械门控离子通道介导的机械转导在脑功能中的重要性还没有得到充分认识。在这里，我们发现机械门控 Piezo1 通道在星形胶质细胞的探索过程中表达，并利用其机械敏感性来介导机械诱发的 Ca 反应和 ATP 释放，从而在星形胶质细胞中建立 Piezo1 介导的机械-化学转导。星形胶质细胞中的 Piezo1 缺失会导致海马体体积和脑重量显著减少，并严重损害体内成年神经发生（但可通过 ATP 挽救），并且在体外完全消除了 ATP 依赖性增强神经干细胞（NSC）增殖。Piezo1 缺失小鼠表现出海马长时程增强（LTP）和学习记忆行为受损。相比之下，星形胶质细胞中 Piezo1 的过表达足以增强机械转导、LTP 和学习记忆能力。因此，星形胶质细胞利用 Piezo1 介导的机械转导机制来强有力地调节成年神经发生和认知功能，从概念上强调了机械转导在大脑结构和功能中的重要性。
