Pharmacological targeting of bunyavirus-induced synaptic impairment prevents neuronal hyperexcitability
Abstract
Orthobunyaviruses are linked to a broad spectrum of neurological disorders. However, the molecular determinants governing bunyavirus neuropathogenesis remain poorly understood, precluding the identification of drugs able to alleviate virus-induced neuronal dysfunctions. Here, we show that the prevalent, yet neglected, orthobunyavirus Ťahyňa virus (TAHV) disrupts neuronal integrity and proteostasis in human cerebral organoids (hCO), significantly decreasing synaptic protein expression and density. Moreover, TAHV-induced synaptic remodeling is associated with perturbed local field potential in organotypic cultures of human post-mortem adult brain explants (OPAB) and higher expression of the metabotropic Glutamate receptor 1 (mGluR1) in mice in the absence of overt neurological disease or neuroinflammation. Using proteome-based network medicine, we identified gabapentin as a therapeutic candidate that restores neurotransmitter receptor levels back to baseline in mice, and prevents TAHV-induced hyperexcitability in OPAB. Together, our data highlights the underappreciated neuropathological potential of a neglected orthobunyavirus, that interferes with neural integrity and neurotransmission, while neuromodulatory interventions may help to preserve cerebral functions.
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BibTeX
@article{gorda2026pharmacological,
title = {{Pharmacological targeting of bunyavirus-induced synaptic impairment prevents neuronal hyperexcitability}},
author = {Barbara Gorda and Jules Bouget and Vaishali Saini and Willy Lutz and Aurélie Hirschler and Glaucia Maria Almeida and Diana Brychka and Corentin Bernou and Emma Partiot and François Delalande and Pramesh Sinha and Hamendra Singh Parmar and Solange Desagher and Gowrishankar Ganesh and Hem Chandra Jha and Sophie Colomb and Christine Carapito and Raphael Gaudin},
journal = {Nature Communications},
year = {2026},
month = sep,
doi = {10.1038/s41467-026-77284-8},
url = {https://hal.science/hal-05773164v1},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Pharmacological targeting of bunyavirus-induced synaptic impairment prevents neuronal hyperexcitability
AU - Barbara Gorda
AU - Jules Bouget
AU - Vaishali Saini
AU - Willy Lutz
AU - Aurélie Hirschler
AU - Glaucia Maria Almeida
AU - Diana Brychka
AU - Corentin Bernou
AU - Emma Partiot
AU - François Delalande
AU - Pramesh Sinha
AU - Hamendra Singh Parmar
AU - Solange Desagher
AU - Gowrishankar Ganesh
AU - Hem Chandra Jha
AU - Sophie Colomb
AU - Christine Carapito
AU - Raphael Gaudin
PY - 2026
DA - 2026/09/01
JO - Nature Communications
DO - 10.1038/s41467-026-77284-8
UR - https://hal.science/hal-05773164v1
AB - Orthobunyaviruses are linked to a broad spectrum of neurological disorders. However, the molecular determinants governing bunyavirus neuropathogenesis remain poorly understood, precluding the identification of drugs able to alleviate virus-induced neuronal dysfunctions. Here, we show that the prevalent, yet neglected, orthobunyavirus Ťahyňa virus (TAHV) disrupts neuronal integrity and proteostasis in human cerebral organoids (hCO), significantly decreasing synaptic protein expression and density. Moreover, TAHV-induced synaptic remodeling is associated with perturbed local field potential in organotypic cultures of human post-mortem adult brain explants (OPAB) and higher expression of the metabotropic Glutamate receptor 1 (mGluR1) in mice in the absence of overt neurological disease or neuroinflammation. Using proteome-based network medicine, we identified gabapentin as a therapeutic candidate that restores neurotransmitter receptor levels back to baseline in mice, and prevents TAHV-induced hyperexcitability in OPAB. Together, our data highlights the underappreciated neuropathological potential of a neglected orthobunyavirus, that interferes with neural integrity and neurotransmission, while neuromodulatory interventions may help to preserve cerebral functions.
SN - 2041-1723
SN - 2041-1723
ER -