Abstract
Pyramidal cell spike block is a common occurrence in migraine with aura and epileptic seizures. In both cases, pyramidal cells experience hyperexcitation with rapidly increasing firing rates, major changes in electrochemistry, and ultimately spike block that temporarily terminates neuronal activity. In cortical spreading depression (CSD), spike block propagates as a slowly traveling wave of inactivity through cortical pyramidal cells, which is thought to precede migraine attacks with aura. In seizures, highly synchronized cortical activity can be interspersed with, or terminated by, spike block. While the identifying characteristic of CSD and seizures is the pyramidal cell hyperexcitation, it is currently unknown how the dynamics of the cortical microcircuits and inhibitory interneurons affect the initiation of hyperexcitation and subsequent spike block.
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. We discuss the implications that localized effects on cortical interneurons have beyond the isolated microcircuit and their contribution to CSD and epileptic seizures.
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Data availability
Data is available in tabular form on request.
Code availability
Our model is available for download on ModelDB (accession number 267033; http://modeldb.yale.edu/267033).
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Stein, W., Harris, A.L. Interneuronal dynamics facilitate the initiation of spike block in cortical microcircuits. J Comput Neurosci 50, 275–298 (2022). https://doi.org/10.1007/s10827-022-00815-x
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DOI: https://doi.org/10.1007/s10827-022-00815-x