摘要：SummaryA subset of glutamatergic neurons in the forebrain uses labile Zn2+as a co-transmitter alongside glutamate. Synaptic Zn2+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 Zn2+binding site that selectively eliminates zinc inhibition of NMDA receptors. Ablation of Zn2+-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 Zn2+negatively modulates spatial cognition by dampening GluN2A-containing NMDA receptor signaling.Graphical abstractDisplay OmittedHighlights•Zn2+inhibits NMDA receptors via high-affinity binding site on the GluN2A subunit•Disruption of Zn2+-GluN2A binding improves contextual fear learning in mice•Loss of Zn2+action on GluN2A improves short-term spatial memory formation•Disruption of Zn2+-GluN2A binding enhances hippocampal place cell representationBiological sciences; Neuroscience; Behavioral neuroscience; Molecular neuroscience.
