Abstract
The dynamics of higher-order topological signals are increasingly recognized as a key aspect of the activity of complex systems. A paradigmatic example are synaptic dynamics: synaptic efficacy changes over time driven by different mechanisms. Beyond traditional node-driven short-term plasticity, the role of astrocyte modulation through higher-order interactions, in the tripartite synapse, is increasingly recognized. However, the competition and interplay between node-driven and higher-order mechanisms remain poorly understood. Here, we introduce a higher-order model of the tripartite synapse, accounting for astrocyte-synapse-neuron interactions in short-term plasticity, such that astrocyte gliotransmission and pre-synaptic facilitation jointly modulate neurotransmitter release, generalizing earlier short-term plasticity models. We study these mechanisms in a minimal recurrent motif—a directed ring of three excitatory neurons—where one neuron receives external stimulation. Due to strong recurrence, the circuit is prone to self-sustained activity, often ignoring external input. By introducing higher-order interactions via astrocyte modulation, we show this robustly stabilizes circuit dynamics and expands the parameter space supporting stimulus-driven activity. Our findings highlight how astrocytes reshape effective connectivity through higher-order interactions—even in simple recurrent circuits.
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Data availability
All data supporting the findings of this study were generated from numerical simulations of the model described in the “Methods” section. These data can be reproduced using the code provided and are therefore not separately archived. Example outputs are available from the corresponding author upon reasonable request.
Code availability
The code used to perform the simulations and generate the results is publicly available97.
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Acknowledgements
This work has been supported by Grant No. PID2023-149174NB-I00 financed by the Spanish Ministry and Agencia Estatal de Investigación MICIU/AEI/10.13039/501100011033 and ERDF funds (European Union) (to A.P.M. and J.J.T.). A.P.M. also acknowledges financial support by the ‘Ramón y Cajal’ program of the Spanish Ministry of Science and Innovation (Grant RYC2021-031241-I). G.M. would like to thank the “Programa Nacional de Becas de Postgrados en el Exterior “Don Carlos Antonio López”—BECAL” of the Ministry of Economy and Finance of Paraguay for the financial sponsorship to pursue his doctoral studies in the Physics and Mathematics Program of the University of Granada. We thank Maurizio De Pittà for his valuable feedback on this manuscript, which helped enhance both its clarity and depth through his thoughtful comments and suggestions.
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A.P.M., G.M. and J.J.T. conceived the study. G.M. and J.J.T. developed the theoretical framework and computational methodology, and designed the numerical experiments. G.M. implemented the model, performed the simulations, conducted the data analysis, visualization and interpretation of the results. G.M., A.P.M. and J.J.T. wrote the original draft of the manuscript. G.M. and J.J.T. contributed to manuscript revision and provided critical feedback. J.J.T. supervised the project, and acquired funding.
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Menesse, G., Millán, A.P. & Torres, J.J. Astrocyte-mediated higher-order control of synaptic plasticity. Commun Biol (2026). https://doi.org/10.1038/s42003-026-10044-y
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DOI: https://doi.org/10.1038/s42003-026-10044-y
