Plasticity in the functional properties of NMDA receptors improves network stability during severe energy stress.
Plasticity in the functional properties of NMDA receptors improves network stability during severe energy stress.
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NMDA 受体功能特性的可塑性提高了网络在严重能量压力下的稳定性。
DOI：
10.1101/2023.01.19.524811
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Santin,JosephM
中科院分区：
文献类型：
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作者：
Bueschke,Nikolaus;Amaral-Silva,Lara;Hu,Min;Alvarez,Alvaro;Santin,JosephM
大脑能量应激导致神经元过度兴奋，随后迅速丧失功能和细胞死亡。相比之下，青蛙脑干会切换到一种极端代谢恢复能力的状态，使它们在从冬眠中苏醒时能够在缺氧期间保持运动功能。 NMDA 受体 (NMDAR) 是 Ca2+ 渗透性谷氨酸受体，会导致缺氧期间体内平衡的丧失。因此，我们假设冬眠会导致可塑性降低，从而降低 NMDAR 在神经网络中改善缺氧期间功能的作用。为了测试这一点，我们评估了一个大量涉及 NMDAR 突触的回路，即雌性牛蛙 Lithobates catesbeianus 的脑干呼吸网络。与我们的预期相反，冬眠并没有改变 NMDAR 在生成网络输出中的作用，也没有影响 NMDAR 电流的幅度、动力学和缺氧敏感性。相反，冬眠强烈降低了 NMDAR Ca2+ 渗透性，并增强了重复刺激过程中的脱敏作用。在严重缺氧的情况下，正常的 NMDAR 分布会在几分钟内引起网络过度兴奋，通过阻断 NMDAR 可以缓解这种情况。冬眠后，NMDAR 的修饰补体可以防止过度兴奋，因为在缺氧状态下至少一小时内不会出现紊乱的输出。这些发现揭示了 NMDAR 可塑性的状态依赖性，即受体功能的多种变化可改善代谢应激期间的神经性能，而不会干扰其在健康条件下的正常作用。
Brain energy stress leads to neuronal hyperexcitability followed by a rapid loss of function and cell death. In contrast, the frog brainstem switches into a state of extreme metabolic resilience that allows them to maintain motor function during hypoxia as they emerge from hibernation. NMDA receptors (NMDARs) are Ca2+-permeable glutamate receptors that contribute to the loss of homeostasis during hypoxia. Therefore, we hypothesized that hibernation leads to plasticity that reduces the role of NMDARs within neural networks to improve function during hypoxia. To test this, we assessed a circuit with a large involvement of NMDAR synapses, the brainstem respiratory network of female bullfrogs,Lithobates catesbeianus. Contrary to our expectations, hibernation did not alter the role of NMDARs in generating network output, nor did it affect the amplitude, kinetics, and hypoxia sensitivity of NMDAR currents. Instead, hibernation strongly reduced NMDAR Ca2+permeability and enhanced desensitization during repetitive stimulation. Under severe hypoxia, the normal NMDAR profile caused network hyperexcitability within minutes, which was mitigated by blocking NMDARs. After hibernation, the modified complement of NMDARs protected against hyperexcitability, as disordered output did not occur for at least one hour in hypoxia. These findings uncover state-dependence in the plasticity of NMDARs, whereby multiple changes to receptor function improve neural performance during metabolic stress without interfering with their normal role during healthy conditions.