Triheteromeric N-methyl-d-aspartate receptors differentiate synaptic inputs onto pyramidal neurons in somatosensory cortex: Involvement of the GluN3A subunit

N-methyl-d-aspartate receptors (NMDARs) are glutamatergic by virtue of glutamate-binding GluN2 subunits and glycinergic by virtue of glycine-binding GluN1 and GluN3 subunits. The existence, location, and functional-significance of NMDARs containing both GluN2 and GluN3 subunits have as yet remained unelucidated. Here we report on the discovery and characterization of a novel type of NMDARs, found at layer (L)1/primary whisker-motor-cortex inputs onto L5 pyramidal neurons in somatosensory cortex, that are distinct in structure and function from conventional GluN2A-containing NMDARs at thalamic/striatal (Str) inputs onto the same neurons. These receptors had a threshold-like activation at hyperpolarized holding-potentials with strong outward rectification of their current–voltage relationships unlike any known GluN1/GluN2-containing NMDARs. Pharmacology revealed a triheteromeric-receptor with features common to glutamate-activated GluN1/GluN2-containing and glycine-activated GluN1/GluN3-containing diheteromeric NMDARs. However, unlike GluN1/GluN3 receptors, NMDARs at L1 inputs were activated by glutamate and blocked by d-AP5, Ca2+-permeable, and more efficient at integrating and potentiating EPSPs selectively over Str inputs during high-frequency stimulation while obviating the need for AMPAR-mediated depolarization.

Graphical abstractFigure optionsDownload full-size imageDownload high-quality image (95 K)Download as PowerPoint slideHighlights► Discovery and characterization of a novel type of triheteromeric NMDA receptor. ► Unique voltage-dependent properties distinguish this receptor from traditional NMDARs. ► Differences in synaptic NMDAR subunit-composition globally manifest in L5-pyramids. ► Incorporation of GluN3A alters biophysical and physiological properties of traditional NMDARs.