Microglial-Mediated Prevention of Axonal Degeneration in the Injured Spinal Cord: Insights from an In Vivo Imaging Study

ABSTRACT Microglia, the primary immune cells in the central nervous system, play a critical role in regulating neuronal function and fate through their interaction with neurons. Despite extensive research, the specific functions and mechanisms of microglia-neuron interactions remain incompletely understood. In this study, we demonstrate that microglia establish direct contact with myelinated axons at Nodes of Ranvier in the spinal cord of mice. Under normal physiological conditions, microglia-node contact occurs in a random scanning pattern and is associated with neuronal activity. However, in response to axonal injury, microglia rapidly transform their contact into a robust wrapping form, preventing acute axonal degeneration from extending beyond the nodes. This neuroprotective wrapping behavior of microglia is dependent on the function of their P2Y12 receptors, which may be activated by ATP released through axonal volume-activated anion channels at the nodes. Additionally, voltage-gated sodium channels (NaV) contribute to the interaction between nodes and glial cells following injury, and inhibition of NaV delays axonal degeneration. Through in vivo imaging, our findings reveal a neuroprotective role of microglia during the acute phase of spinal cord injury, achieved through a novel form of neuron-glia interaction.