title: Molecular and genetic determinants of the NMDA receptor for superior learning and memory functions.
abstract: The opening-duration of the NMDA receptors implements Hebb's synaptic coincidence-detection and is long thought to be the rate-limiting factor underlying superior memory. Here, we investigate the molecular and genetic determinants of the NMDA receptors by testing the "synaptic coincidence-detection time-duration" hypothesis vs. "GluN2B intracellular signaling domain" hypothesis. Accordingly, we generated a series of GluN2A, GluN2B, and GluN2D chimeric subunit transgenic mice in which C-terminal intracellular domains were systematically swapped and overexpressed in the forebrain excitatory neurons. The data presented in the present study supports the second hypothesis, the "GluN2B intracellular signaling domain" hypothesis. Surprisingly, we found that the voltage-gated channel opening-durations through either GluN2A or GluN2B are sufficient and their temporal differences are marginal. In contrast, the C-terminal intracellular domain of the GluN2B subunit is necessary and sufficient for superior performances in long-term novel object recognition and cued fear memories and superior flexibility in fear extinction. Intriguingly, memory enhancement correlates with enhanced long-term potentiation in the 10-100 Hz range while requiring intact long-term depression capacity at the 1-5 Hz range.
authors.affiliation: Brain and Behavior Discovery Institute and Department of Neurology, Medical College of Georgia at Georgia Regents University, Augusta, Georgia, United States of America.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Jacobs
authors.affiliation: Brain and Behavior Discovery Institute and Department of Neurology, Medical College of Georgia at Georgia Regents University, Augusta, Georgia, United States of America.
authors.forename: Zhenzhong
authors.initials: Z
authors.lastname: Cui
authors.affiliation: Brain and Behavior Discovery Institute and Department of Neurology, Medical College of Georgia at Georgia Regents University, Augusta, Georgia, United States of America.
authors.forename: Ruiben
authors.initials: R
authors.lastname: Feng
authors.affiliation: Shanghai Institute of Functional Genomics, East China Normal University, Shanghai, China.
authors.forename: Huimin
authors.initials: H
authors.lastname: Wang
authors.affiliation: Banna Biomedical Research Institute, Xi-Shuang-Ban-Na Prefecture, Yunnan Province, China.
authors.forename: Deheng
authors.initials: D
authors.lastname: Wang
authors.affiliation: Brain and Behavior Discovery Institute and Department of Neurology, Medical College of Georgia at Georgia Regents University, Augusta, Georgia, United States of America.
authors.forename: Joe Z
authors.initials: JZ
authors.lastname: Tsien
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001522:Behavior, Animal; D056547:CA1 Region, Hippocampal / Q000502:physiology; D003463:Cues; D055724:Electrophysiological Phenomena; D005239:Fear / Q000502:physiology; D017774:Long-Term Potentiation / Q000502:physiology; D008568:Memory / Q000502:physiology*; D057567:Memory, Long-Term / Q000502:physiology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009474:Neurons / Q000378:metabolism; D016548:Prosencephalon / Q000378:metabolism; D021122:Protein Subunits / Q000737:chemistry / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: D021122:Protein Subunits; D016194:Receptors, N-Methyl-D-Aspartate