Downregulation of NR3A-containing NMDARs is required for synapse maturation and memory consolidation.
NR3A is the only NMDA receptor (NMDAR) subunit that downregulates sharply prior to the onset of sensitive periods for plasticity, yet the functional importance of this transient expression remains unknown. To investigate whether removal/replacement of juvenile NR3A-containing NMDARs is involved in experience-driven synapse maturation, we used a reversible transgenic system that prolonged NR3A expression in the forebrain. We found that removal of NR3A is required to develop strong NMDAR currents, full expression of long-term synaptic plasticity, a mature synaptic organization characterized by more synapses and larger postsynaptic densities, and the ability to form long-term memories. Deficits associated with prolonged NR3A were reversible, as late-onset suppression of transgene expression rescued both synaptic and memory impairments. Our results suggest that NR3A behaves as a molecular brake to prevent the premature strengthening and stabilization of excitatory synapses and that NR3A removal might thereby initiate critical stages of synapse maturation during early postnatal neural development.
Roberts
Adam C
AC
Department of Cell and Molecular Physiology, Neuroscience Center, and Neurodevelopmental Disorders Research Center, University of North Carolina, Chapel Hill, NC 27599, USA.
Díez-García
Javier
J
Rodriguiz
Ramona M
RM
López
Iciar Paula
IP
Luján
Rafael
R
Martínez-Turrillas
Rebeca
R
Picó
Esther
E
Henson
Maile A
MA
Bernardo
Danilo R
DR
Jarrett
Thomas M
TM
Clendeninn
Dallis J
DJ
López-Mascaraque
Laura
L
Feng
Guoping
G
Lo
Donald C
DC
Wesseling
John F
JF
Wetsel
William C
WC
Philpot
Benjamin D
BD
Pérez-Otaño
Isabel
I
D000818:Animals; D000831:Animals, Newborn; D001703:Biophysics; D000076122:Disks Large Homolog 4 Protein; D015536:Down-Regulation / Q000502:physiology*; D004558:Electric Stimulation / Q000379:methods; D005518:Food Preferences / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000235:genetics; D051528:Guanylate Kinases; D006624:Hippocampus / Q000166:cytology; D047468:Immunoprecipitation / Q000379:methods; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D018782:Maze Learning / Q000502:physiology; D008565:Membrane Proteins / Q000378:metabolism; D008568:Memory / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission / Q000379:methods; D009473:Neuronal Plasticity / Q000235:genetics / Q000502:physiology; D009474:Neurons / Q000166:cytology* / Q000648:ultrastructure; D018408:Patch-Clamp Techniques / Q000379:methods; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*; D021641:Recognition, Psychology / Q000502:physiology; D016622:Silver Staining / Q000379:methods; D012919:Social Behavior; D013569:Synapses / Q000502:physiology*; D055366:Synaptic Potentials / Q000235:genetics / Q000502:physiology
D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C464437:NR3A NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D049452:Green Fluorescent Proteins; D051528:Guanylate Kinases
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