The unconventional N-methyl-d-aspartate (NMDA) receptor subunits GluN3A and GluN3B
can, when associated with the other glycine-binding subunit GluN1, generate excitatory
conductances purely activated by glycine. However, functional GluN1/GluN3 receptors
have not been identified in native adult tissues. We discovered that GluN1/GluN3A
receptors are operational in neurons of the mouse adult medial habenula (MHb), an
epithalamic area controlling aversive physiological states. In the absence of glycinergic
neuronal specializations in the MHb, glial cells tuned neuronal activity via GluN1/GluN3A
receptors. Reducing GluN1/GluN3A receptor levels in the MHb prevented place-aversion
conditioning. Our study extends the physiological and behavioral implications of glycine
by demonstrating its control of negatively valued emotional associations via excitatory
glycinergic NMDA receptors.
