Determinants of Optogenetic Cortical Spreading Depolarizations

TLDR

Cortical spreading depolarization underlies migraine aura and contributes to secondary brain injury, yet existing experimental models are highly invasive and often cause tissue damage, limiting their translational relevance. The study introduces a non‑invasive optogenetic method to trigger cortical spreading depolarizations in transgenic mice expressing channelrhodopsin‑2. By delivering 470‑nm light (1–10 mW) through an optical fiber to the intact skull, the authors induce power‑dependent extracellular potential shifts and potassium elevations that trigger SD once a threshold is exceeded. The model shows that homozygous ChR2 mice have lower light thresholds for SD, cortical region susceptibility decreases from motor to visual cortex and correlates with ChR2 expression, and the NMDA antagonist MK‑801 blocks SD onset without altering extracellular potential shifts, underscoring its suitability for studying SD modulation.

Abstract

Cortical spreading depolarization (SD) is the electrophysiological event underlying migraine aura, and a critical contributor to secondary damage after brain injury. Experimental models of SD have been used for decades in migraine and brain injury research; however, they are highly invasive and often cause primary tissue injury, diminishing their translational value. Here we present a non-invasive method to trigger SDs using light-induced depolarization in transgenic mice expressing channelrhodopsin-2 in neurons (Thy1-ChR2-YFP). Focal illumination (470 nm, 1-10 mW) through intact skull using an optical fiber evokes power-dependent steady extracellular potential shifts and local elevations of extracellular [K+] that culminate in an SD when power exceeds a threshold. Using the model, we show that homozygous mice are significantly more susceptible to SD (i.e., lower light thresholds) than heterozygous ChR2 mice. Moreover, we show SD susceptibility differs significantly among cortical divisions (motor, whisker barrel, sensory, visual, in decreasing order of susceptibility), which correlates with relative channelrhodopsin-2 expression. Furthermore, the NMDA receptor antagonist MK-801 blocks the transition to SD without diminishing extracellular potential shifts. Altogether, our data show that the optogenetic SD model is highly suitable for examining physiological or pharmacological modulation of SD in acute and longitudinal studies.