Bueschke Nikolaus, Amaral-Silva Lara, Hu Min, Alvarez Alvaro, Santin Joseph M
University of Missouri, Columbia, MO 65201.
University of North Carolina-Greensboro, Greensboro, NC 27402.
bioRxiv. 2023 Oct 16:2023.01.19.524811. doi: 10.1101/2023.01.19.524811.
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 Ca-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 energy stress. To test this, we assessed a circuit with a large involvement of NMDAR synapses, the brainstem respiratory network of female bullfrogs, . 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 Ca 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 energy stress without interfering with its normal role during healthy activity.
脑能量应激会导致神经元过度兴奋，随后功能迅速丧失和细胞死亡。相比之下，青蛙脑干会转变为一种极端的代谢适应状态，使其在从冬眠中苏醒时处于缺氧状态下仍能维持运动功能。N-甲基-D-天冬氨酸受体（NMDARs）是钙离子通透的谷氨酸受体，在缺氧期间会导致体内稳态的丧失。因此，我们推测冬眠会导致可塑性变化，减少神经网络中NMDARs的作用，以在能量应激期间改善功能。为了验证这一点，我们评估了一个大量涉及NMDAR突触的回路，即雌性牛蛙的脑干呼吸网络。与我们的预期相反，冬眠并没有改变NMDARs在产生网络输出中的作用，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的钙离子通透性，并增强了重复刺激期间的脱敏作用。在严重缺氧的情况下，正常的NMDAR特征会在几分钟内导致网络过度兴奋，通过阻断NMDARs可减轻这种情况。冬眠后，NMDARs的改变后的组成防止了过度兴奋，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NMDARs可塑性的状态依赖性，即受体功能的多种变化在能量应激期间改善神经性能，而不干扰其在健康活动中的正常作用。
