Different Ras isoforms regulate synaptic plasticity in opposite directions
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.
Authors
- Alba Fernández‐Rodrigo (ORCID: https://orcid.org/0000-0003-3834-0687)
- David Fernández de Sevilla (ORCID: https://orcid.org/0000-0001-6344-0773)
- Víctor Briz (ORCID: https://orcid.org/0000-0001-6936-0918)
- Alberto Fernández‐Medarde (ORCID: https://orcid.org/0000-0002-1230-5501)
- Carmen Guerra (ORCID: https://orcid.org/0000-0002-3891-046X)
- José A. Esteban (ORCID: https://orcid.org/0000-0002-3759-3300)
- Mariano Barbacid (ORCID: https://orcid.org/0000-0002-1480-2624)
- Silvia Gutiérrez-Eisman
- Jessie G Jiang (ORCID: https://orcid.org/0000-0001-7389-6539)
- Esperanza López-Merino (ORCID: https://orcid.org/0009-0004-2265-9858)
- Eugenio Santos (ORCID: https://orcid.org/0000-0003-3565-0321)
Institutions
- Université de Bordeaux (FR)
- Inserm (FR)
- Universidad de Salamanca (ES)
- Instituto de Salud Carlos III (ES)
- Spanish National Cancer Research Centre (ES)
- Centro Nacional de Sanidad Ambiental (ES)
- Neurocentre Magendie (FR)
- Centro de Investigación del Cáncer (ES)
- Centro de Biología Molecular Severo Ochoa (ES)
- Centro de Investigación Biomédica en Red de Cáncer (ES)
- Universidad Autónoma de Madrid (ES)
Publication Details
- Journal
- The EMBO Journal
- Published
- 2025-02-21
- DOI
- https://doi.org/10.1038/s44318-025-00390-8
- Citations
- 1
- Primary Topic
- Neuroscience and Neuropharmacology Research
- Type
- article
- Field-Weighted Citation Impact
- 0.91
Funders
- Fundación Ramón Areces
- Ministerio de Ciencia, Innovación y Universidades
- Instituto de Salud Carlos III