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. 2025 Aug 1:273:110434.
doi: 10.1016/j.neuropharm.2025.110434. Epub 2025 Mar 26.

Acute stress enhances synaptic plasticity in male mice via a microbiota-dependent mechanism

Cristina Rosell-Cardona  1 , Michael K Collins  2 , Kenneth J O'Riordan  1 , Michael S Goodson  3 , Nancy Kelley-Loughnane  3 , John F Cryan  2 , Gerard Clarke  4
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Free article

Acute stress enhances synaptic plasticity in male mice via a microbiota-dependent mechanism

Cristina Rosell-Cardona et al. Neuropharmacology. .
Free article

Abstract

Acute stress can enhance or impair synaptic plasticity depending on the nature, duration, and type of stress exposure as well as the brain region examined. The absence of a gut microbiome can also alter hippocampal plasticity. However, the possible interplay between synaptic plasticity, acute stress, and the gut microbiota remains unknown. Here, we examine this interaction and determine whether the gut microbiota impacts stress-induced alterations in hippocampal plasticity. Further, we explored whether exposure to the microbial metabolite butyrate is sufficient to counteract stress-induced alterations in synaptic plasticity. We used electrophysiological and molecular experiments in adult male C57/BL6 antibiotic-treated and acutely stressed mice. In electrophysiological experiments we treated hippocampal slices with 3 μM sodium butyrate to explore the effect of this microbial metabolite. We found the presence of the microbiota essential for the enhancement of both short- and long-term potentiation induced by 15 min of acute restraint stress. Furthermore, butyrate exposure effectively restored the stress-induced enhancement of potentiation in slices from microbiome-depleted animals while also enhancing long-term potentiation independent of stress. In addition, alterations of hippocampal synaptic plasticity markers were noted. Our findings highlight a critical new temporal role for gut-derived metabolites in defining the impact of acute stress on synaptic plasticity.

Keywords: Acute stress; Gut-brain axis; Microbiota; Synaptic plasticity.

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Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The research was conducted in the APC Microbiome Ireland which is funded by Science Foundation Ireland (now Research Ireland, SFI/12/RC/2273_P2). This project reports financial support was provided by European Office of Aerospace Research and Development, Air Force Office of Scientific Research and 711 Human Performance Wing, Air Force Research Laboratory. The views expressed are those of the authors and do not reflect the official views of the United States Air Force, nor the Department of Defense. Mention of trade names, commercial products, or organizations do not imply endorsement by the U.S. Government (Distribution Statement A. Approved for public release. Distribution is unlimited. Case Number: AFRL-2024-6130, Nov 20, 2024). John F. Cryan reports a relationship with Bromotech that includes: speaking and lecture fees. John F. Cryan reports a relationship with Reckitt that includes: funding grants. John F. Cryan reports a relationship with Nutricia Research BV that includes: funding grants. John F. Cryan reports a relationship with DuPont Nutrition & Biosciences that includes: funding grants. John F. Cryan reports a relationship with Nestle that includes: funding grants. Ger Clarke reports a relationship with Janssen Pharmaceuticals Inc that includes: funding grants. Ger Clarke reports a relationship with Probi AB that includes: funding grants. Ger Clarke reports a relationship with Boehringer Ingelheim GmbH that includes: speaking and lecture fees. Ger Clarke reports a relationship with Apsen Farmacêutica SA that includes: funding grants. Ger Clarke reports a relationship with Pharmavite LLC that includes: funding grants. Ger Clarke reports a relationship with Fonterra Research and Development Centre that includes: funding grants. Ger Clarke reports a relationship with Tate and Lyle that includes: funding grants. Ger Clarke reports a relationship with Nestle that includes: funding grants. Ger Clarke reports a relationship with Yakult Central Research Institute for Microbiological Research that includes: paid expert testimony. Ger Clarke reports a relationship with Heel Pharmaceuticals that includes: paid expert testimony. Ger Clarke reports a relationship with Zentiva Group a s that includes: paid expert testimony. Kenneth J. O'Riordan has received honoraria from Sanofi Genzyme and Danone. This support neither influenced nor constrained the contents of this manuscript. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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