Pathway-specific differences in subunit composition of synaptic NMDA receptors on pyramidal neurons in neocortex

Heterogeneity of synaptic inputs onto neocortical layer 5 pyramidal neurons could result from differences in the underlying receptors, yet previous work has shown that functional attributes of AMPA receptors are uniform among synaptic connections onto these neurons. To determine whether NMDA receptors (NMDARs) would be similarly uniform, we compared in the same pyramidal neurons pharmacologically isolated NMDAR-mediated EPSCs evoked by stimulation of two anatomically distinguishable pathways, callosal or intracortical. Based on differences in voltage dependence, decay kinetics, apparent Mg2+ sensitivity, and subunit-specific (NR2A, NR2B, and NR2C/D) pharmacology, we found NMDARs at these inputs to be distinct. Furthermore, NMDARs activated by the intracortical pathway were more efficient at integrating EPSPs and bringing the neuron closer to the spike-firing threshold than the callosal pathway. These results suggest that pyramidal neurons encode information differentially depending on the origin of their neocortical inputs and that NMDAR-dependent synaptic plasticity may be pathway specific.