Identity of Endogenous NMDAR Glycine Site Agonist in Amygdala Is Determined by Synaptic Activity Level

Mechanisms of NMDA receptor-dependent synaptic plasticity contribute to the acquisition and retention of conditioned fear memory. However, synaptic rules which may determine the extent of NMDA receptor activation in the amygdala, a key structure implicated in fear learning, remain unknown. Here we show that the identity of the NMDAR glycine site agonist at synapses in the lateral nucleus of the amygdala may depend on the level of synaptic activation. Tonic activation of NMDARs at synapses in the amygdala under low-activity conditions is supported by ambient D-serine, whereas glycine may be released from astrocytes in response to afferent impulses. The release of glycine may decode the increases in afferent activity levels into enhanced NMDAR-mediated synaptic events, serving an essential function in the induction of NMDAR-dependent long-term potentiation in fear conditioning pathways.