Zn Inhibits Spatial Memory and Hippocampal Place Cell Representation Through High-affinity Binding to the NMDA Receptor GluN2A Subunit

A subset of glutamatergic neurons in the forebrain uses labile Zn as a co-transmitter alongside glutamate. Synaptic Zn plays a key role in learning and memory processes, but its mechanisms of action remain poorly understood. Here, we used a knock-in (KI) mouse line carrying a point mutation at the GluN2A Zn binding site that selectively eliminates zinc inhibition of NMDA receptors. Ablation of Zn-GluN2A binding improves spatial memory retention and contextual fear memory formation. Electrophysiological recording of hippocampal neurons in the CA1 area revealed a greater proportion of place cells and substantial place field remapping in KI mice compared to wildtype littermates. Persistent place cell remapping was also seen in KI mice upon repeated testing suggesting an enhanced ability to maintain a distinct representation across multiple overlapping experiences. Together, these findings reveal an original molecular mechanism through which synaptic Zn negatively modulates spatial cognition by dampening GluN2A-containing NMDA receptor signaling.