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A role for the Ras signalling pathway in synaptic transmission and long-term memory

Nature volume 390, pages 281–286 (1997)Cite this article

Abstract

Members of the Ras subfamily of small guanine-nucleotide-binding proteins are essential for controlling normal and malignant cell proliferation as well as cell differentiation1. The neuronal-specific guanine-nucleotide-exchange factor, Ras-GRF/CDC25Mm (refs 2,3,4), induces Ras signalling in response to Ca2+ influx5 and activation of G-protein-coupled receptors in vitro6, suggesting that it plays a role in neurotransmission and plasticity in vivo7. Here we report that mice lacking Ras-GRF are impaired in the process of memory consolidation, as revealed by emotional conditioning tasks that require the function of the amygdala; learning and short-term memory are intact. Electrophysiological measurements in the basolateral amygdala reveal that long-term plasticity is abnormal in mutant mice. In contrast, Ras-GRF mutants do not reveal major deficits in spatial learning tasks such as the Morris water maze, a test that requires hippocampal function. Consistent with apparently normal hippocampal functions, Ras-GRF mutants show normal NMDA (N-methyl-D-aspartate) receptor-dependent long-term potentiation in this structure. These results implicate Ras-GRF signalling via the Ras/MAP kinase pathway in synaptic events leading to formation of long-term memories.

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Figure 1: Generation of a targeted mutation in the mouse Ras-GRF gene.
Figure 2: Ras-GRF mutant mice do not show gross morphological abnormalities in the brain.
Figure 3: Impaired memory consolidation in Ras-GRF mutant mice during fear conditioning tests.
Figure 4: Hippocampal-dependent behaviour appears to be normal in Ras-GRF mutant mice.
Figure 5: Figure 5 Impaired synaptic plasticity in the amygdala of Ras-GRF−/− mice.

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Acknowledgements

We thank F. Casagranda for her help with ES cell work, A. Plück, K. Brennan and M.Lemaistre for generating germline chimaeras from the second independent ES cell clone, K.-P. Giese and A. Silva for providing their Ras-GRF mouse mutant strain before publication, R. Morris, R. Zippel, E.Martegani, L. Alberghina, A. Oliverio and P. Orban for critically reading the manuscript and F. Peverali for helping with artwork. R.B. was supported by a long-term Human Frontier Science Program Organization (HFSPO) postdoctoral fellowship, L.M. by a long-term EMBO fellowship, S.G.N.G. and C.H. by the Wellcome Trust, and A.R. by BBSRC. The work was partially supported by the Italian Association for Cancer Research (AIRC), by Progetto Finalizzato ACRO of the Italian National Research Council (CNR) and by CEE (to E.S.), by the Swiss National Science Foundation (to H.-P.L. and D.P.W.), by HFSPO (to H.-P.L. and S.G.N.G.) and by MRC (to P.F.C.).

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Author notes

  1. Riccardo Brambilla, Nerina Gnesutta and Clelia Rossi-Arnaud: These authors contributed equally to this work.

Authors and Affiliations

  1. European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117, Heidelberg, Germany

    Riccardo Brambilla, Liliana Minichiello & Rdiger Klein

  2. Dipartimento di Fisiologia e Biochimica Generali, Universita' di Milano, 20133, Milano, Italy

    Nerina Gnesutta & Emmapaola Sturani

  3. Physiology Unit, School of Molecular and Medical Biosciences, University of Wales, Cardiff, CF1 3US>, UK

    Gail White & Paul F. Chapman

  4. Centre for Genome Research, University of Edinburgh, Edinburgh, EH9 3JQ, UK

    Alistair J. Roylance, Caroline E. Herron & Seth G. N. Grant

  5. Centre for Neuroscience, University of Edinburgh, Edinburgh, EH8 9LE, UK

    Caroline E. Herron, Mark Ramsey & Seth G. N. Grant

  6. Anatomisches Institut, Universität Zürich, CH-8057, Zürich, Switzerland

    David P. Wolfer & Hans-Peter Lipp

  7. Istituto di Psicobiologia e Psicofarmacologia del Consiglio Nazionale delle Ricerche, 00198, Roma, Italy

    Vincenzo Cestari

  8. Dipartimento di Psicologia, Universita' di Roma La Sapienza, 00185, Roma, Italy

    Clelia Rossi-Arnaud

  9. DIBIT, Istituto Scientifico San Raffaele, Via Olgettina 58, 20132, Milano, Italy

    Riccardo Brambilla

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Correspondence to Rdiger Klein.

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Brambilla, R., Gnesutta, N., Minichiello, L. et al. A role for the Ras signalling pathway in synaptic transmission and long-term memory. Nature 390, 281–286 (1997). https://doi.org/10.1038/36849

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