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Updated: Jun 3, 2025

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Progesterone receptors regulate susceptibility to spreading depression.

Suchitra Joshi1, John Williamson1, Serapio M Baca2

  • 1Department of Neurology, University of Virginia, Charlottesville, VA 22908, USA.

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|January 8, 2025
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Summary

Progesterone receptor signaling critically regulates cortical spreading depression (CSD), the mechanism behind migraine auras. Activating progesterone receptors increases CSD, while blocking them or genetic deletion suppresses it.

Keywords:
Cortical spreading depression (CSD)MigraineProgesterone receptorsRU-486Somatosensory cortexhM4Di

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Area of Science:

  • Neuroscience
  • Endocrinology
  • Migraine Pathophysiology

Background:

  • Migraine with aura is linked to cortical spreading depression (CSD).
  • Progesterone receptor (PR) signaling influences migraine susceptibility.
  • The role of PR in regulating CSD remains unclear.

Purpose of the Study:

  • To investigate whether progesterone receptor (PR) signaling regulates susceptibility to cortical spreading depression (CSD).

Main Methods:

  • Utilized female mice (gonadally-intact and ovariectomized, estrogen-primed) with varying PR expression.
  • Induced CSD via KCl application and recorded cortical activity.
  • Modulated PR with segesterone (agonist) and RU-486 (antagonist).
  • Assessed PR expression in somatosensory cortex using AAV9-flex-GFP.
  • Evaluated CSD susceptibility after chemogenetic silencing of PR-expressing neurons.

Main Results:

  • PRs are expressed in excitatory somatosensory cortical neurons, predominantly in layers 4-6.
  • PR activation by segesterone increased CSD frequency and propagation speed.
  • PR antagonism with RU-486 or genetic deletion of PRs suppressed CSD.
  • Chemogenetic silencing of PR-expressing neurons reduced CSD frequency.

Conclusions:

  • Progesterone-PR signaling critically regulates CSD susceptibility.
  • This highlights a key mechanism in female hormonal regulation of migraine.
  • Findings advance understanding of migraine pathophysiology.