Neuron
Article
Subunit Composition of Synaptic AMPA Receptors Revealed by a Single-Cell Genetic Approach
Wei Lu,1 Yun Shi,1 Alexander C. Jackson,1 Kirsten Bjorgan,1 Matthew J. During,2 Rolf Sprengel,3 Peter H. Seeburg,3 and Roger A. Nicoll1,*
of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94143, USA of Molecular Virology, Immunology, and Medical Genetics, Ohio State University, Columbus, OH 43210, USA 3Department of Molecular Neurobiology, Max Planck Institute for Medical Research, D-69120 Heidelberg, Germany *Correspondence: nicoll@cmp.ucsf.edu DOI 10.1016/j.neuron.2009.02.027
2Department 1Department
SUMMARY
The precise subunit composition of synaptic ionotropic receptors in the brain is poorly understood. This information is of particular importance with regard to AMPA-type glutamate receptors, the multimeric complexes assembled from GluA1-A4 subunits, as the trafcking of these receptors into and out of synapses is proposed to depend upon the subunit composition of the receptor. We report a molecular quantication of synaptic AMPA receptors (AMPARs) by employing a single-cell genetic approach coupled with electrophysiology in hippocampal CA1 pyramidal neurons. In contrast to prevailing views, we nd that GluA1A2 heteromers are the dominant AMPARs at CA1 cell synapses ($80%). In cells lacking GluA1, -A2, and -A3, synapses are devoid of AMPARs, yet synaptic NMDA receptors (NMDARs) and dendritic morphology remain unchanged. These data demonstrate a functional dissociation of AMPARs from trafcking of NMDARs and neuronal morphogenesis. This study provides a functional quantication of the subunit composition of AMPARs in the CNS and suggests novel roles for AMPAR subunits in receptor trafcking.
INTRODUCTION The advent of molecular biology and receptor cloning has resulted in extraordinary advances in our understanding of neurotransmitter receptors. Virtually all ionotropic receptors are multimeric structures composed of variable combinations of subunits. The function and trafcking of these receptors are critically dependent on their subunit composition. Based on the biophysical properties of heterologously expressed receptors; the expression pattern of the subunits; conventional gene knockout (KO) approaches; and, in rare instances, the discovery of subunit selective antagonists, the subunit composition of native synaptic receptors has been inferred but not unambiguously established. We have focused on determining the subunit composition of AMPA-type ionotropic glutamate receptors (AMPARs) at the

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