title: Acquisition of contextual discrimination involves the appearance of a RAS-GRF1/p38 mitogen-activated protein (MAP) kinase-mediated signaling pathway that promotes long term potentiation (LTP).
abstract: RAS-GRF1 is a guanine nucleotide exchange factor with the ability to activate RAS and RAC GTPases in response to elevated calcium levels. We previously showed that beginning at 1 month of age, RAS-GRF1 mediates NMDA-type glutamate receptor (NMDAR)-induction of long term depression in the CA1 region of the hippocampus of mice. Here we show that beginning at 2 months of age, when mice first acquire the ability to discriminate between closely related contexts, RAS-GRF1 begins to contribute to the induction of long term potentiation (LTP) in the CA1 hippocampus by mediating the action of calcium-permeable, AMPA-type glutamate receptors (CP-AMPARs). Surprisingly, LTP induction by CP-AMPARs through RAS-GRF1 occurs via activation of p38 MAP kinase rather than ERK MAP kinase, which has more frequently been linked to LTP. Moreover, contextual discrimination is blocked by knockdown of Ras-Grf1 expression specifically in the CA1 hippocampus, infusion of a p38 MAP kinase inhibitor into the CA1 hippocampus, or the injection of an inhibitor of CP-AMPARs. These findings implicate the CA1 hippocampus in the developmentally dependent capacity to distinguish closely related contexts through the appearance of a novel LTP-supporting signaling pathway.
authors.affiliation: Department of Biochemistry, Tufts University School of Medicine, Boston, Massachusetts 02111, USA.
authors.forename: Shan-Xue
authors.initials: SX
authors.lastname: Jin
authors.forename: Junko
authors.initials: J
authors.lastname: Arai
authors.forename: Xuejun
authors.initials: X
authors.lastname: Tian
authors.forename: Rajendra
authors.initials: R
authors.lastname: Kumar-Singh
authors.forename: Larry A
authors.initials: LA
authors.lastname: Feig
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D056547:CA1 Region, Hippocampal / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D004192:Discrimination, Psychological / Q000502:physiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism / Q000502:physiology; D009570:Nitriles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D034622:RNA Interference; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020666:ras-GRF1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000218:Adamantane; D002070:Butadienes; D002118:Calcium; D048049:Extracellular Signal-Regulated MAP Kinases; D007093:Imidazoles; D009570:Nitriles; D011725:Pyridines; D018091:Receptors, AMPA; D048051:p38 Mitogen-Activated Protein Kinases; D020666:ras-GRF1; C110702:IEM 1460; C113580:U 0126; C093642:SB 203580
keywords: Glutamate Receptors Ionotropic (AMPA, NMDA); Hippocampus; Neurobiology; Neurons; RAS; RAS-GRF; Signal Transduction; Synaptic Plasticity; p38 MAPK