UC San Diego

The NMDA receptor is a key excitatory receptor in the brain and essential for synaptic plasticity, the cellular correlate of learning and memory. It was demonstrated that this ionotropic receptor can also signal without ion-flux. However, the role of specific NMDA receptor subunits and the influence of sex is still unclear. In this study, we did electrophysiology in acute brain slices and investigated the process of hippocampal ion-flux independent LTD (long-term synaptic depression). We found that young female mice do not exhibit ion-flux independent LTD after LFS (low frequency stimulation). However, upon estrogen receptor blockade, we did observe ion-flux independent LTD, suggesting a protective role of estrogen receptors in female mice. In contrast, ion-flux independent LTD was present in young male mice and required the GluN2B subunit of the NMDA receptor. These findings indicate that ion-flux independent LTD functions through different mechanisms in male and female mice.