Distinct Modulation of High- and Low-Frequency Activity by Midazolam and Neurosteroids in Neocortical Slices
Stefan Bieletzki1, Clara Gotthard1, Xènia Puig-Bosch2,3
1Department of Anesthesiology and Intensive Care Medicine, Experimental Anesthesiology Section, Eberhard Karls University, 72076 Tübingen, Germany.
International Journal of Molecular Sciences
|August 13, 2026
Summary
Neurosteroids, unlike benzodiazepines, do not suppress high-frequency brain activity (HFA) mediated by α1-GABAA receptors. This suggests neurosteroids may offer a safer alternative to benzodiazepines by selectively targeting low-frequency activity (LFA).
Area of Science:
- Neuroscience
- Pharmacology
- Molecular Biology
Background:
- Adverse effects of benzodiazepines are primarily linked to GABAA receptors containing α1-subunits.
- Neurosteroids are emerging as potential replacements for benzodiazepines, but their interaction with α1-GABAA receptors requires clarification.
- Understanding how neurosteroids modulate neuronal activity, particularly α1-GABAA receptor-controlled activity, is crucial for developing safer therapeutics.
Purpose of the Study:
- To investigate the differential effects of a benzodiazepine (midazolam) and neurosteroids (allopregnanolone and XBD173) on high-frequency activity (HFA) and low-frequency activity (LFA).
- To determine if neurosteroids, like benzodiazepines, upregulate or affect α1-GABAA receptors.
- To compare the modulation of α1-GABAA receptor-mediated neuronal activity by benzodiazepines versus neurosteroids.
Main Methods:
- Extracellular multi-unit recordings were performed on cultured neocortical tissue slices from wild-type and α2/3/5-knock-in mice.
- The effects of midazolam, allopregnanolone, and XBD173 on HFA (>50 Hz) and LFA (<50 Hz) were compared.
- Midazolam's effects were specifically assessed in α2/3/5-knock-in mice, where it acts almost exclusively via α1-GABAA receptors.
Main Results:
- Midazolam selectively suppressed HFA in both wild-type and α2/3/5-knock-in mice, confirming its action via α1-GABAA receptors.
- Allopregnanolone and XBD173 did not affect HFA.
- Allopregnanolone and XBD173 significantly suppressed LFA, indicating a distinct mechanism of action compared to midazolam.
Conclusions:
- Neurosteroids, unlike benzodiazepines, do not dampen HFA, a network activity tightly controlled by α1-GABAA receptors.
- Benzodiazepines and neurosteroids exert differential control over distinct frequency bands of cortical network activity.
- Neurosteroids may offer a safer therapeutic profile by avoiding the suppression of HFA, potentially reducing some adverse effects associated with benzodiazepines.
