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

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.