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The Journal of Neuroscience, July 11, 2007, 27(28):7365-7376; doi:10.1523/JNEUROSCI.0956-07.2007

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Cellular/Molecular
Distinct Structural and Ionotropic Roles of NMDA Receptors in Controlling Spine and Synapse Stability

Veronica A. Alvarez, Dennis A. Ridenour, and Bernardo L. Sabatini

Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115

Correspondence should be addressed to Dr. Bernardo L. Sabatini, Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115. Email: bernardo_sabatini{at}hms.harvard.edu

NMDA-type glutamate receptors (NMDARs) play a central role in the rapid regulation of synaptic transmission, but their contribution to the long-term stabilization of glutamatergic synapses is unknown. We find that, in hippocampal pyramidal neurons in rat organotypic slices, pharmacological blockade of NMDARs does not affect synapse formation and dendritic spine growth but does increase the motility of spines. Physical loss of synaptic NMDARs induced by RNA interference against the NR1 subunit of the receptor also increases the motility of spines. Furthermore, knock-down of NMDARs, but not their pharmacological block, destabilizes spine structure and over time leads to loss of spines and excitatory synapses. Maintenance of normal spine density requires the coexpression of two specific splice isoforms of the NR1 subunit that contain the C-terminal C2 cassette. Thus, although ionotropic properties of NMDARs induce synaptic plasticity, it is the physical interactions of the C-tail of the receptor that mediate the long-term stabilization of synapses and spines.

Key words: NMDAR; AMPAR; synapse stability; dendritic spines; hippocampus; NR1 splice variants

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Received March 2, 2007; revised May 28, 2007; accepted May 29, 2007.

Correspondence should be addressed to Dr. Bernardo L. Sabatini, Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115. Email: bernardo_sabatini{at}hms.harvard.edu

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