Plasticity in the Functional Properties of NMDA Receptors Improves Network Stability during Severe Energy Stress

• Published in: The Journal of neuroscience Vol. 44; no. 9; p. e0502232024
• Main Authors: Bueschke, Nikolaus, Amaral-Silva, Lara, Hu, Min, Alvarez, Alvaro, Santin, Joseph M
• Format: Journal Article
• Language: English
• Published: United States Society for Neuroscience 28.02.2024
• Subjects: Brain stem; Calcium ions; Calcium permeability; Cell death; Desensitization; Female; Functional plasticity; Glutamic acid receptors; Glutamic acid receptors (ionotropic); Hibernation; Homeostasis; Humans; Hypoxia; Metabolism; N-Methyl-D-aspartic acid receptors; Neural networks; Neuronal Plasticity - physiology; Plastic properties; Plasticity; Receptor mechanisms; Receptors; Receptors, N-Methyl-D-Aspartate - metabolism; Synapses; Synapses - physiology; brain metabolism; hypoxia; hypoxia tolerance; synaptic plasticity; NMDA receptor; Ca2
• ISSN: 0270-6474; 1529-2401; 1529-2401
• DOI: 10.1523/JNEUROSCI.0502-23.2024

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 hypoxia. 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 metabolic stress without interfering with their normal role during healthy conditions.