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

TLDR

Spreading depolarization is a massive, self‑sustaining wave of brain cell depolarization, and although NMDA receptors were thought to drive it, their precise role remains unclear due to limitations of traditional pharmacology. The study seeks to clarify the role of NMDA receptors in spreading depolarization to inform treatment of stroke and migraine aura. Using single‑cell blockade and genetic deletion of NMDA receptors in hippocampal CA1 neurons, the authors isolated their contribution to depolarization without disrupting wave propagation. They found that NMDA receptors are not required to initiate spreading depolarization but are essential for sustaining it, as their inhibition accelerates recovery of membrane potential and input resistance during the late phase.

Abstract

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.