Investigating the role of GluN2D-containing NMDARs in BNST excitatory signaling: Implications for regulating cell-specific synaptic function and the modulation of affective behaviors

Abstract

Excitatory signaling mediated by N-methyl-d-aspartate receptors (NMDARs) has been shown to regulate mood disorders. However, current treatments targeting NMDAR subtypes have shown limited success in treating patients, highlighting a need for alternative therapeutic targets. Here, we identify a role for GluN2D-containing NMDARs in modulating emotional behaviors and neural activity in the bed nucleus of the stria terminalis (BNST). Using a GluN2D knockout mouse line (GluN2D-/-), we assessed behavioral phenotypes across tasks modeling emotional behavior. We then used a combination of ex vivo electrophysiology and in vivo fiber photometry to assess changes in BNST plasticity, cell-specific physiology and cellular activity profiles. GluN2D-/- male mice exhibit evidence of exacerbated negative emotional behavior, and a deficit in BNST synaptic potentiation. We also found that GluN2D is functionally expressed on corticotropin-releasing factor (CRF) positive BNST cells implicated in driving negative emotional states, and recordings in mice of both sexes revealed increased excitatory and reduced inhibitory drive onto GluN2D-/- BNST-CRF cells ex vivo, and increased activity in vivo. Using a GluN2D conditional knockout line (GluN2Dflx/flx) to selectively delete the subunit from the BNST, we find that BNST-GluN2Dflx/flx male mice exhibit increased depressive-like behaviors, as well as altered NMDAR function and increased excitatory drive onto BNST-CRF neurons. Taken together, this study supports a role for GluN2D-NMDARs in regulating emotional behavior through their influence on excitatory signaling in a region-specific manner, and suggests that these NMDARs may serve as a novel target for selectively modulating glutamate signaling in stress-responsive structures and cell populations.