Abstract
The GluN3A subunit of N-methyl-D-aspartate receptors (NMDARs) plays an established role in synapse development, but its contribution to neural circuits in the adult brain is less clear. Recent work has demonstrated that in select cell populations, GluN3A assembles with GluN1 to form GluN1/GluN3A receptors that are insensitive to glutamate and instead serve as functional excitatory glycine receptors (eGlyRs). Our understanding of these eGlyRs, and how they contribute to intrinsic excitability and synaptic communication within relevant networks of the developing and the mature brain, is only beginning to be uncovered. Here, using male and female mice, we demonstrate that GluN3A subunits are enriched in the adult ventral hippocampus (VH), where they localize to synaptic and extrasynaptic sites and can assemble as functional eGlyRs on CA1 pyramidal cells. GluN3A expression was barely detectable in the adult dorsal hippocampus (DH). We also observed a high GluN2B content in the adult VH, characterized by slow NMDAR current decay kinetics and a high sensitivity to the GluN2B-containing NMDAR antagonist ifenprodil. Interestingly, the GluN2B enrichment in the adult VH was dependent on GluN3A as GluN3A deletion accelerated NMDAR decay and reduced ifenprodil sensitivity in the VH, suggesting that GluN3A expression can regulate the balance of conventional NMDAR subunit composition at synaptic sites. Lastly, we found that GluN3A knockout also enhanced both NMDAR-dependent calcium influx and NMDAR-dependent long-term potentiation in the VH. Together, these data reveal a novel role for GluN3A and eGlyRs in the control of ventral hippocampal circuits in the mature brain.
Significance statement Glutamate is the brain’s most abundant excitatory neurotransmitter. One of its most common receptors is the NMDA receptor (NMDAR), composed of a variety of subunits. Here, we show that an atypical NMDAR subunit, GluN3A, is enriched in the ventral hippocampus, where it forms a receptor that is no longer sensitive to glutamate. Instead, it acts as an excitatory receptor for glycine, normally an inhibitory transmitter. We show that GluN3A plays essential roles in the adult ventral hippocampus, modulating transmitter release probability, conventional NMDAR subunit composition, calcium entry, and synaptic plasticity. These findings are important as they shed light on the role of GluN3A and these newly discovered excitatory glycine receptors in the mature brain.
