NMDA receptors sustain but do not initiate neuronal depolarization in spreading depolarization

• Published in: Neurobiology of disease Vol. 145; p. 105071
• Main Authors: Mei, Yu-Ying, Lee, Ming-Hsueh, Cheng, Ting-Chun, Hsiao, I-Han, Wu, Dong Chuan, Zhou, Ning
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2020; Elsevier
• Subjects: Grin1 knockout; Input resistance; Membrane potential; NMDA receptors; Spreading depolarization; Input resistance; Membrane potential; Spreading depolarization; NMDA receptors; Grin1 knockout
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2020.105071

Spreading depolarization (SD) represents a neurological process characterized by a massive, self-sustaining wave of brain cell depolarization. Understanding its mechanism is important for treating ischemic or hemorrhagic stroke and migraine with aura. Many believed that ion fluxes through NMDA receptors (NMDARs) are responsible for neuronal transmembrane currents of SD. However, the explicit role of NMDARs remains ambiguous. This is in part due to the limitation of traditional pharmacological approaches in resolving the contribution of NMDARs in different intercellular and intracellular processes of SD. Here, we applied single-cell blockade and genetic deletion methods to remove functional NMDARs from individual hippocampal CA1 neurons in order to examine the role of NMDARs in the depolarization mechanism without affecting the propagation of SD. We analyzed neuronal membrane potential changes to demonstrate that NMDARs are not required for initiating the depolarization. Consistently, neuronal input resistance (RN) revealed a sharp decline at the start of SD, which was unaffected by blocking NMDARs. Instead, the recovery of both membrane potential and RN during the late phase of SD was facilitated by inhibition of NMDARs, indicating that NMDARs are responsible for sustaining the depolarization. Our results strongly indicate that NMDAR activation is not a determinant of the initiation of depolarization but is important for sustaining transmembrane ion fluxes during SD. •Neuronal depolarization during SD consists of early phase and late sustained phase.•Single-cell dialysis of MK-801 inhibits NMDAR responses and the late phase of SD.•Knockout of functional NMDARs affects the late but not early depolarization phase.•Blocking NMDARs does not prevent rapid reduction in Rin but facilitates its recovery.