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The Journal of Neuroscience, September 23, 2009, 29(38):11965-11972; doi:10.1523/JNEUROSCI.2109-09.2009

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Cellular/Molecular
NMDA Receptor Phosphorylation at a Site Affected in Schizophrenia Controls Synaptic and Behavioral Plasticity

Bo Li,^2 * Nino Devidze,^1 * Denis Barengolts,¹ Naseem Prostak,³ Eleana Sphicas,¹ Alfonso J. Apicella,² Roberto Malinow,⁴ and Effat S. Emamian^1,5

¹The Rockefeller University, New York, New York 10021, ²Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, ³Cell & Molecular Technologies, Phillipsburg, New Jersey 08865, ⁴Department of Neuroscience, University of California, San Diego, La Jolla, California 92093-0634, and ⁵Advanced Technologies for Novel Therapeutics (ATNT), LLC., Newark, New Jersey 07103

Correspondence should be addressed to Effat S. Emamian, Advanced Technologies for Novel Therapeutics (ATNT), LLC., 211 Warren Street, Newark, NJ 07103. Email: emame{at}atnt-usa.com

Phosphorylation of the NR1 subunit of NMDA receptors (NMDARs) at serine (S) 897 is markedly reduced in schizophrenia patients. However, the role of NR1 S897 phosphorylation in normal synaptic function and adaptive behaviors are unknown. To address these questions, we generated mice in which the NR1 S897 is replaced with alanine (A). This knock-in mutation causes severe impairment in NMDAR synaptic incorporation and NMDAR-mediated synaptic transmission. Furthermore, the phosphomutant animals have reduced AMPA receptor (AMPAR)-mediated synaptic transmission, decreased AMPAR GluR1 subunit in the synapse, and impaired long-term potentiation. Finally, the mutant mice exhibit behavioral deficits in social interaction and sensorimotor gating. Our results suggest that an impairment in NR1 phosphorylation leads to glutamatergic hypofunction that can contribute to behavioral deficits associated with psychiatric disorders.

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Received May 4, 2009; revised July 13, 2009; accepted Aug. 10, 2009.

Correspondence should be addressed to Effat S. Emamian, Advanced Technologies for Novel Therapeutics (ATNT), LLC., 211 Warren Street, Newark, NJ 07103. Email: emame{at}atnt-usa.com

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