Metabotropic NMDAR Signaling Contributes to Sex Differences in Synaptic Plasticity and Episodic Memory.

NMDA receptor (NMDAR) - mediated calcium influx triggers the induction and initial expression of Long-Term Potentiation (LTP). Here we report that in male rodents ion flux-independent (metabotropic) NMDAR signaling is critical for a third step in the production of enduring LTP, i.e., cytoskeletal changes that stabilize the activity-induced synaptic modifications. Surprisingly, females rely upon estrogen receptor alpha (ERα) for the metabotropic NMDAR operations used by males. Blocking NMDAR channels with MK-801 eliminated LTP expression in hippocampal field CA1 of both sexes but left intact theta burst stimulation (TBS)-induced actin polymerization within dendritic spines. A selective antagonist (Ro25-6981) of the NMDAR GluN2B subunit had minimal effects on synaptic responses but blocked actin polymerization and LTP consolidation in males only. Conversely, an ERα antagonist thoroughly disrupted TBS-induced actin polymerization and LTP in females while having no evident effect in males. In an episodic memory paradigm, Ro25-6981 prevented acquisition of spatial locations by males but not females whereas an ERα antagonist blocked acquisition in females but not males. Sex differences in LTP consolidation were accompanied by pronounced differences in episodic memory in tasks involving a minimal (for learning) cue-sampling. Males did better on acquisition of spatial information whereas females had much higher scores than males on tests for acquisition of the identity of cues (episodic 'what') and the order in which the cues were sampled (episodic 'when'). We propose that sex differences in synaptic processes used to stabilize LTP result in differential encoding of the basic elements of episodic memory.Significance Statement Calcium influx through NMDARs has long been recognized as the initiating event for LTP. Results of the present studies call for a substantial revision to this fundamental observation about learning-related synaptic plasticity. Specifically, we show cytoskeletal mechanisms that consolidate field CA1 LTP and episodic memory are triggered not by NMDAR-mediated calcium but by ion flux-independent (metabotropic) signaling. Males used metabotropic functions of the NMDARs for this purpose whereas females relied upon synaptic estrogen receptors. This unprecedented instance of sex differences in synaptic function was accompanied by surprisingly large male/female differences in the acquisition of the three basic elements of episodic memory.