title: R-Ras contributes to LTP and contextual discrimination.
abstract: The ability to discriminate between closely related contexts is a specific form of hippocampal-dependent learning that may be impaired in certain neurodegenerative disorders such as Alzheimer's and Down Syndrome. However, signaling pathways regulating this form of learning are poorly understood. Previous studies have shown that the calcium-dependent exchange factor Ras-GRF1, an activator of Rac, Ras and R-Ras GTPases, is important for this form of learning and memory. Moreover, the ability to discriminate contexts was linked to the ability of Ras-GRF1 to promote high-frequency stimulation long-term potentiation (HFS-LTP) via the activation of p38 Map kinase. Here, we show that R-Ras is involved in this form of learning by using virally-delivered miRNAs targeting R-Ras into the CA1 region of the dorsal hippocampus and observing impaired contextual discrimination. Like the loss of GRF1, knockdown of R-Ras in the CA1 also impairs the induction of HFS-LTP and p38 Map kinase. Nevertheless, experiments indicate that this involvement of R-Ras in HFS-LTP that is required for contextual discrimination is independent of Ras-GRF1. Thus, R-Ras is a novel regulator of a form of hippocampal-dependent LTP as well as learning and memory that is affected in certain forms of neurodegenerative diseases.
authors.affiliation: Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, MA, United States.
authors.forename: M J
authors.initials: MJ
authors.lastname: Darcy
authors.affiliation: Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, MA, United States.
authors.forename: S-X
authors.initials: SX
authors.lastname: Jin
authors.affiliation: Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, MA, United States; Department of Neuroscience, Tufts University School of Medicine, Boston, MA, United States. Electronic address: larry.feig@tufts.edu.
authors.forename: L A
authors.initials: LA
authors.lastname: Feig
mesh_terms: D000818:Animals; D056547:CA1 Region, Hippocampal / Q000502:physiology*; D004192:Discrimination, Psychological / Q000502:physiology*; D004558:Electric Stimulation / Q000379:methods; D046352:Freezing Reaction, Cataleptic / Q000502:physiology; D055785:Gene Knockdown Techniques; D007150:Immunohistochemistry; D036881:Long-Term Synaptic Depression / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs; D041681:NIH 3T3 Cells; D046509:Tissue Culture Techniques; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*; D020666:ras-GRF1 / Q000378:metabolism
chemical_list: D035683:MicroRNAs; C513037:Rasgrf1 protein, mouse; D020666:ras-GRF1; D048051:p38 Mitogen-Activated Protein Kinases; C513254:Rras protein, mouse; D018631:ras Proteins
keywords: Ras-GRF1; hippocampus; synaptic plasticity