title: Hippocampal NMDA receptor subunits differentially regulate fear memory formation and neuronal signal propagation.
abstract: Activation of NMDA receptors (NMDAR) in the hippocampus is essential for the formation of contextual and trace memory. However, the role of individual NMDAR subunits in the molecular mechanisms contributing to these memory processes is not known. Here we demonstrate, using intrahippocampal injection of subunit-selective compounds, that the NR2A-preferring antagonist impaired contextual and trace fear conditioning as well as learning-induced increase of the nuclear protein c-Fos. The NR2B-specific antagonist, on the other hand, selectively blocked trace fear conditioning without affecting c-Fos levels. Studies with cultured primary hippocampal neurons, further showed that synaptic and extrasynaptic NR2A and NR2B differentially regulate the extracellular signal-regulated kinase 1 and 2/mitogen- and stress-activated protein kinase 1 (ERK1/2/MSK1)/c-Fos pathway. Activation of the synaptic population of NMDAR induced cytosolic, cytoskeletal, and perinuclear phosphorylation of ERK1/2 (pERK1/2). The nuclear propagation of pERK1/2 signals, revealed by upregulation of the downstream nuclear targets pMSK1 and c-Fos, was blocked by a preferential NR2A but not by a specific NR2B antagonist. Conversely, activation of total (synaptic and extrasynaptic) NMDAR engaged receptors with NR2B subunits, and resulted in membrane retention of pERK1/2 without inducing pMSK1 and c-Fos. Stimulation of extrasynaptic NMDAR alone was consistently ineffective at activating ERK signaling. The discrete contribution of synaptic and total NR2A- and NR2B-containing NMDAR to nuclear transmission vs. membrane retention of ERK signaling may underlie their specific roles in the formation of contextual and trace fear memory.
authors.affiliation: Department of Psychiatry and Behavioral Sciences and The Asher Center for the Study and Treatment of Depressive Disorders, Chicago, Illinois, USA. can-gao@northwestern.edu
authors.forename: Can
authors.initials: C
authors.lastname: Gao
authors.forename: Martin B
authors.initials: MB
authors.lastname: Gill
authors.forename: Natalie C
authors.initials: NC
authors.lastname: Tronson
authors.forename: Anita L
authors.initials: AL
authors.lastname: Guedea
authors.forename: Yomayra F
authors.initials: YF
authors.lastname: Guzmán
authors.forename: Kyu Hwan
authors.initials: KH
authors.lastname: Huh
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Corcoran
authors.forename: Geoffrey T
authors.initials: GT
authors.lastname: Swanson
authors.forename: Jelena
authors.initials: J
authors.lastname: Radulovic
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000201:enzymology / Q000378:metabolism / Q000502:physiology; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D005239:Fear / Q000502:physiology*; D005260:Female; D006624:Hippocampus / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008297:Male; D008568:Memory / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D009435:Synaptic Transmission / Q000502:physiology
chemical_list: C120997:NR2A NMDA receptor; C121001:NR2B NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D048049:Extracellular Signal-Regulated MAP Kinases