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, Ca(2+)-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.
Department of Biomedical Sciences, College of Medicine & Program in Neuroscience, Florida State University, 1115 West Call Street, Tallahassee, FL 32306-4300, United States.
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D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000465:Algorithms; D000818:Animals; D002118:Calcium / Q000378:metabolism; D004558:Electric Stimulation; D055724:Electrophysiological Phenomena; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D018698:Glutamic Acid / Q000378:metabolism; D005998:Glycine / Q000378:metabolism; D066298:In Vitro Techniques; D007474:Ion Exchange; D007700:Kinetics; D008274:Magnesium / Q000378:metabolism; D009434:Neural Pathways / Q000502:physiology; D017966:Pyramidal Cells / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000502:physiology*; D013003:Somatosensory Cortex / Q000187:drug effects / Q000502:physiology*; D013569:Synapses / Q000187:drug effects / Q000502:physiology*
D018691:Excitatory Amino Acid Antagonists; C464437:NR3A NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D015763:2-Amino-5-phosphonovalerate; D008274:Magnesium; D002118:Calcium; D005998:Glycine