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)
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)
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.
- Boston University United States
- Tufts University United States
Mice, Knockout, Neurons, Time Factors, Pyridines, Long-Term Potentiation, Imidazoles, Adamantane, p38 Mitogen-Activated Protein Kinases, Mice, Inbred C57BL, Mice, Discrimination, Psychological, Nitriles, Butadienes, Animals, Calcium, RNA Interference, Receptors, AMPA, Extracellular Signal-Regulated MAP Kinases, CA1 Region, Hippocampal, Signal Transduction
Mice, Knockout, Neurons, Time Factors, Pyridines, Long-Term Potentiation, Imidazoles, Adamantane, p38 Mitogen-Activated Protein Kinases, Mice, Inbred C57BL, Mice, Discrimination, Psychological, Nitriles, Butadienes, Animals, Calcium, RNA Interference, Receptors, AMPA, Extracellular Signal-Regulated MAP Kinases, CA1 Region, Hippocampal, Signal Transduction
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