2026-06-14T03:43:11Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/265712025-12-18T13:00:00Zcom_20.500.12105_2052com_20.500.12105_2051col_20.500.12105_19610

00925njm 22002777a 4500 dc López-Merino, Esperanza author Fernández-Rodrigo, Alba author Jiang, Jessie G author Gutiérrez-Eisman, Silvia author Fernández de Sevilla, David author Fernández-Medarde, Alberto author Santos, Eugenio author Guerra, Carmen author Barbacid, Mariano author Esteban, José A author Briz, Víctor author 2025-02-21 The small GTPase Ras is an intracellular signaling hub required for long-term potentiation (LTP) in the hippocampus and for memory formation. Genetic alterations in Ras signaling (i.e., RASopathies) are linked to cognitive disorders in humans. However, it remains unclear how Ras controls synaptic plasticity, and whether different Ras isoforms play overlapping or distinct roles in neurons. Using genetically modified mice, we show here that H-Ras (the most abundant isoform in the brain) does not promote LTP, but instead long-term depression mediated by metabotropic glutamate receptors (mGluR-LTD). Mechanistically, H-Ras is activated locally in spines during mGluR-LTD via c-Src, and is required to trigger Erk activation and de novo protein synthesis. Furthermore, H-Ras deletion impairs object recognition as well as social and spatial memory. Conversely, K-Ras is the isoform specifically required for LTP. This functional specialization correlates with a differential synaptic distribution of the two isoforms H-Ras and K-Ras, which may have important implications for RASopathies and cognitive function. López-Merino E, Fernández-Rodrigo A, Jiang JG, Gutiérrez-Eisman S, Fernández de Sevilla D, Fernández-Medarde A, Santos E, Guerra C, Barbacid M, Esteban JA, Briz V. Different Ras isoforms regulate synaptic plasticity in opposite directions. EMBO J. 2025 Feb 21. 10.1038/s44318-025-00390-8 1460-2075 0261-4189 The EMBO journal 39984756 https://hdl.handle.net/20.500.12105/26571 Hippocampus Memory RASopathies Spine mGluR Different Ras isoforms regulate synaptic plasticity in opposite directions