Pharmacological targeting of bunyavirus-induced synaptic impairment prevents neuronal hyperexcitability

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. his study reveals the neuropathologic potential of the neglected Tahyna virus, and presents a powerful pipeline to discover antivirals that target the consequences of an infection (disorder oriented) rather than the infection itself (viro-centric). Funding: Human Frontiers Science Program (HFSP) grant (RGP012/2024-101) to RG and GG. PEPR ANRS MIE as part of the France 2030 program (project ViroBrain, reference ANRS-24-PEPRMIE-0006) to RG and CC. Agence Nationale de la Recherche ANR MigraVir (AN... [1640 chars]