Temporal memory and its enhancement by estradiol requires surface dynamics of hippocampal CA1 NMDA receptors

Background: Identifying the underlying cellular mechanisms of episodic memory is an important challenge since this memory, based on temporal and contextual associations among events, undergoes preferential degradation in aging and various neuropsychiatric disorders. Memory storage of temporal and contextual associations is known to rely on hippocampal NMDA receptor (NMDAR)dependent synaptic plasticity, which depends on dynamic organization of surface NMDAR. Whether NMDAR surface trafficking sustains the formation of associative memory remains however unknown. Methods: We tested this hypothesis, using single nanoparticle imaging, in vivo electrophysiology and behavioral approaches in hippocampal networks challenged with a potent modulator of NMDARdependent synaptic plasticity and memory, 17b-estradiol (E2). Results: We demonstrate that E2 modulates NMDAR surface trafficking, a necessary condition for E2-induced potentiation at hippocampal CA1 synapses. Strikingly, CA1 NMDAR surface trafficking controls basal and E2enhanced mnemonic retention of temporal, but not contextual associations. Conclusions: NMDAR surface trafficking controls basal and E2-enhanced mnemonic retention of temporal, but not contextual associations, opening a new and non-canonical research avenue in the physiopathology of cognition.