Target-Specific Expression of Presynaptic NMDA Receptors in Neocortical Microcircuits

Traditionally, NMDA receptors are located postsynaptically; yet, putatively presynaptic NMDA receptors (preNMDARs) have been reported. Although implicated in controlling synaptic plasticity, their function is not well understood and their expression patterns are debated. We demonstrate that, in layer 5 of developing mouse visual cortex, preNMDARs specifically control synaptic transmission at pyramidal cell inputs to other pyramidal cells and to Martinotti cells, while leaving those to basket cells unaffected. We also reveal a type of interneuron that mediates ascending inhibition. In agreement with synapse-specific expression, we find preNMDAR-mediated calcium signals in a subset of pyramidal cell terminals. A tuned network model predicts that preNMDARs specifically reroute information flow in local circuits during high-frequency firing, in particular by impacting frequency-dependent disynaptic inhibition mediated by Martinotti cells, a finding that we experimentally verify. We conclude that postsynaptic cell type determines presynaptic terminal molecular identity and that preNMDARs govern information processing in neocortical columns. ► NMDA receptor calcium supralinearities were imaged in cortical layer 5 neuron boutons ► Presynaptic NMDA receptor specificity is determined by postsynaptic cell identity ► Presynaptic NMDA receptors control information flow in neocortical microcircuits The existence of presynaptic NMDA receptors (preNMDARs) is debated and their functional role is unclear. Buchanan et al. demonstrate that postsynaptic cell identity determines preNMDAR expression and that these receptors specifically impact short-term plasticity and information flow in neocortical microcircuits.