Inhibition mediated by group III metabotropic glutamate receptors regulates habenula activity and defensive behaviors

Anna Maria Ostenrath, Nicholas Faturos, Yağnur Işık Çiftci Çobanoğlu, Bram Serneels, Inyoung Jeong, Ekin Dongel Dayanc, Anja Enz, Francisca Hinrichsen, Aytac Kadir Mutlu, Ricarda Bardenhewer, Suresh Kumar Jetti, Stephan C. F. Neuhauss, Nathalie Jurisch-Yaksi and Emre Yaksi ()
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Anna Maria Ostenrath: Norwegian University of Science and Technology
Nicholas Faturos: Norwegian University of Science and Technology
Yağnur Işık Çiftci Çobanoğlu: Norwegian University of Science and Technology
Bram Serneels: Norwegian University of Science and Technology
Inyoung Jeong: Norwegian University of Science and Technology
Ekin Dongel Dayanc: Norwegian University of Science and Technology
Anja Enz: Department of Molecular Life Sciences
Francisca Hinrichsen: Norwegian University of Science and Technology
Aytac Kadir Mutlu: Norwegian University of Science and Technology
Ricarda Bardenhewer: Norwegian University of Science and Technology
Suresh Kumar Jetti: Neuro-Electronics Research Flanders
Stephan C. F. Neuhauss: Department of Molecular Life Sciences
Nathalie Jurisch-Yaksi: Norwegian University of Science and Technology
Emre Yaksi: Norwegian University of Science and Technology

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract Inhibition plays a key role in brain functions. While typically linked to GABA, inhibition can be induced by glutamate via metabotropic glutamate receptors (mGluRs). Here, we investigated the role of mGluR-mediated inhibition in the habenula, a conserved, glutamatergic brain hub involved in adaptive and defensive behaviors. We found that zebrafish and mice habenula express group III mGluRs. We showed that group III mGluRs regulate membrane potential and calcium activity of zebrafish habenula. Perturbing group III mGluRs increased sensory-evoked excitation and reduced selectivity. We identified inhibition as the primary communication mode among habenula neurons. Blocking group III mGluRs reduces this inhibition and increases neural synchrony. Consistently, we demonstrated that multisensory integration in the habenula relies on competitive suppression, that partly depends on group III mGluRs. Genetic and pharmacological perturbation of group III mGluRs amplified neural responses and defensive behaviors. Our findings highlight an essential role for mGluR-driven inhibition in encoding information and regulating defensive behaviors.

Date: 2025
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DOI: 10.1038/s41467-025-62115-z

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