# Progesterone receptor regulation of seizures

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2022 · $353,281

## Abstract

Abstract
 We propose to test the hypothesis that progesterone receptor (PR) activation enhances the AMPA receptor
(AMPAR)-mediated synaptic transmission of hippocampal principal neurons and increases seizure
susceptibility. Cyclic fluctuations in progesterone levels in women of reproductive age with epilepsy are linked
to catamenial seizure exacerbation. Furthermore, perimenstrual progesterone withdrawal is linked to migraines
and dysphoria. Whether PR activation regulates these disorders is not known.
 Progesterone is historically thought to exert anticonvulsant effects via the potentiation of GABA-A receptor-
mediated inhibition. In contrast, the role of PRs, which are also expressed in the brain, in regulating neuronal
activity is poorly understood outside of the hypothalamic-pituitary axis. Our preliminary studies show that PR
activation increases AMPAR expression in the hippocampus and enhances the AMPAR-mediated synaptic
transmission of CA1 pyramidal neurons. These changes were associated with the increased activity of CA1
neurons. Furthermore, the blockade of PR by the anti-progestin RU-486 or by the genetic deletion of PRs
prevented the observed upregulation of AMPARs. Finally, the specific activation of PRs with a synthetic
agonist, nestorone, increased seizure susceptibility, while RU-486 treatment suppressed neurosteroid
withdrawal-induced seizures in an experimental animal model.
 We propose to directly test the role of PRs in regulating AMPAR expression and the excitability of
hippocampal principal neurons and to assess whether PRs regulate seizure susceptibility.
 In the first aim, we will activate PRs using nestorone in wild-type and knockout animals and determine its
effect on the neuronal excitability and AMPAR-mediated synaptic transmission of CA1 pyramidal neurons and
dentate granule cells, and on the expression of GluA1 and GluA2 subunit proteins and mRNA. We will use
western blotting, qRT-PCR, and electrophysiological techniques in these studies. In the second aim, we will
determine whether PR expression in CA1 neurons and DGCs changes during the estrous cycle, using
fluorescent in situ hybridization assay, qRT-PCR and a mouse expressing myc-tagged PR. In the third aim, we
will test whether PR activation reduces the seizure threshold and alters the susceptibility to status epilepticus
and epileptogenesis by using continuous video-EEG recording.

## Key facts

- **NIH application ID:** 10373003
- **Project number:** 5R01NS110863-04
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Suchitra Joshi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $353,281
- **Award type:** 5
- **Project period:** 2019-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10373003

## Citation

> US National Institutes of Health, RePORTER application 10373003, Progesterone receptor regulation of seizures (5R01NS110863-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10373003. Licensed CC0.

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