NMDA receptor phosphorylation at a site affected in schizophrenia controls synaptic and behavioral plasticity.
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.
The Rockefeller University, New York, New York 10021, USA.
Bo
B
Li
Nino
N
Devidze
Denis
D
Barengolts
Naseem
N
Prostak
Eleana
E
Sphicas
Alfonso J
AJ
Apicella
Roberto
R
Malinow
Effat S
ES
Emamian
D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D001921:Brain / Q000502:physiology / Q000648:ultrastructure; D055879:Gene Knock-In Techniques; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000235:genetics / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020125:Mutation, Missense; D009473:Neuronal Plasticity / Q000235:genetics; D009474:Neurons / Q000502:physiology / Q000648:ultrastructure; D010766:Phosphorylation; D018091:Receptors, AMPA / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics* / Q000378:metabolism*; D012559:Schizophrenia / Q000235:genetics; D012919:Social Behavior; D013569:Synapses / Q000235:genetics / Q000502:physiology / Q000648:ultrastructure; D009435:Synaptic Transmission / Q000235:genetics / Q000502:physiology
D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; C409466:NR1 NMDA receptor