GLUN1/GLUN3A EXCITATORY GLYCINE RECEPTORS CONTROL VENTRAL HIPPOCAMPAL SYNAPTIC PLASTICITY AND ANXIETY-RELATED BEHAVIORS

Excitatory glycine receptors (eGlyRs) have recently emerged as a novel neuronal signaling modality that challenges the traditional view of glycine as a primarily inhibitory neurotransmitter. Composed of the glycine-binding NMDA receptor subunits GluN1 and GluN3A, eGlyRs are insensitive to glutamate and are activated exclusively by glycine. Unlike conventional GluN1/GluN2 NMDARs, the distribution and functional role of eGlyRs remain poorly understood. Previous work from our laboratory and others has demonstrated that eGlyRs are functionally expressed in discrete brain regions, including the medial habenula, basolateral amygdala, and neocortex. Here, combining anatomical, electrophysiological, and behavioral approaches, we investigate eGlyR expression and operation in the adult mouse hippocampus. We show that eGlyRs are highly enriched in the ventral hippocampus (VH), conferring distinct properties to this brain region. eGlyRs display a striking dorsoventral gradient within CA1 pyramidal cells, being expressed in the ventral but not the dorsal hippocampus (VH vs DH). In contrast, SST-positive and PV-positive interneurons express eGlyRs in both subregions. eGlyRs mediate tonic inward currents and regulate neuronal excitability. They are also responsible for the attenuated long-term potentiation (LTP) observed in the VH compared with the DH and are required for the stress hormone corticosterone to control the magnitude of VH LTP. Consistent with their role in VH circuitry and function, eGlyRs contribute to the modulation of anxiety-related behaviors. Overall, our data establish eGlyR signaling as an important modality of intercellular communication in the adult brain, with strong implications for neuropsychiatrically relevant regions involved in internal state regulation and emotional processing.