Interneuronal dynamics facilitate the initiation of cortical spreading depression

Abstract

AbstractCortical spreading depression (CSD) is thought to precede migraine attacks with aura and is characterized by a slowly traveling wave of inactivity through cortical pyramidal cells. During CSD, pyramidal cells experience hyperexcitation with rapidly increasing firing rates, major changes in electrochemistry, and ultimately spike block that propagates slowly across the cortex. While the identifying characteristic of CSD is the pyramidal cell hyperexcitation and subsequent spike block, it is currently unknown how the dynamics of the cortical microcircuits and inhibitory interneurons affect the initiation of CSD.We tested the contribution of cortical inhibitory interneurons to the initiation of spike block using a cortical microcircuit model that takes into account changes in ion concentrations that result from neuronal firing. Our results show that interneuronal inhibition provides a wider dynamic range to the circuit and generally improves stability against spike block.Despite these beneficial effects, strong interneuronal firing contributed to rapidly changing extracellular ion concentrations, which facilitated hyperexcitation and led to spike block first in the interneuron and then in the pyramidal cell. In all cases, a loss of interneuronal firing triggered pyramidal cell spike block. However, preventing interneuronal spike block was insufficient to rescue the pyramidal cell from spike block. Our data thus demonstrate that while the role of interneurons in cortical microcircuits is complex, they are critical to the initiation of pyramidal cell spike block and CSD. We discuss the implications that localized effects on cortical interneurons have beyond the isolated microcircuit.