mGluR5 and NMDA Receptors Drive the Experience- and Activity-Dependent NMDA Receptor NR2B to NR2A Subunit Switch

• Published in: Neuron (Cambridge, Mass.) Mass.), 2011-04, Vol.70 (2), p.339-351
• Main Authors: Matta, Jose A., Ashby, Michael C., Sanz-Clemente, Antonio, Roche, Katherine W., Isaac, John T.R.
• Format: Article
• Language: English
• Subjects: Adaptation, Physiological - physiology; Animals; Animals, Newborn; Electric Stimulation - methods; Electrodes; Enzyme Inhibitors - pharmacology; Estrenes - pharmacology; Excitatory Amino Acid Agonists - pharmacology; Excitatory Amino Acid Antagonists - pharmacology; Excitatory Postsynaptic Potentials - drug effects; Excitatory Postsynaptic Potentials - physiology; Experiments; Female; Hippocampus - cytology; In Vitro Techniques; Kinases; Ligands; Male; Mice; Mice, Knockout; Models, Biological; N-Methylaspartate - pharmacology; Neurons; Piperidines - pharmacology; Pyramidal Cells - drug effects; Pyramidal Cells - physiology; Pyridines - pharmacology; Pyrrolidinones - pharmacology; Quinoxalines - pharmacology; Rats; Rats, Wistar; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate - genetics; Receptors, Metabotropic Glutamate - metabolism; Receptors, N-Methyl-D-Aspartate - physiology; Rodents; Synapses - physiology; Thiazoles - pharmacology; Time Factors; Visual Cortex - physiology
• ISSN: 0896-6273; 1097-4199; 1097-4199
• DOI: 10.1016/j.neuron.2011.02.045

In cerebral cortex there is a developmental switch from NR2B- to NR2A-containing NMDA receptors (NMDARs) driven by activity and sensory experience. This subunit switch alters NMDAR function, influences synaptic plasticity, and its dysregulation is associated with neurological disorders. However, the mechanisms driving the subunit switch are not known. Here, we show in hippocampal CA1 pyramidal neurons that the NR2B to NR2A switch driven acutely by activity requires activation of NMDARs and mGluR5, involves PLC, Ca2+ release from IP3R-dependent stores, and PKC activity. In mGluR5 knockout mice the developmental NR2B-NR2A switch in CA1 is deficient. Moreover, in visual cortex of mGluR5 knockout mice, the NR2B-NR2A switch evoked in vivo by visual experience is absent. Thus, we establish that mGluR5 and NMDARs are required for the activity-dependent NR2B-NR2A switch and play a critical role in experience-dependent regulation of NMDAR subunit composition in vivo. ► The NR2B to 2A subunit switch at CA1 synapses requires NMDARs and mGluR5 ► The NR2 subunit switch requires PLC, IP3, and PKC signaling ► The acute NR2 subunit switch is absent in slices from mGluR5 KO mice ► mGluR5 KO mice exhibit a deficient experience-driven NR2 subunit switch