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Enhanced long-term potentiation and impaired learning in mice with mutant postsynaptic density-95 protein

Nature volume 396, pages 433–439 (1998)Cite this article

Abstract

Specific patterns of neuronal firing induce changes in synaptic strength that may contribute to learning and memory. If the postsynaptic NMDA (N-methyl-D-aspartate) receptors are blocked, long-term potentiation (LTP) and long-term depression (LTD) of synaptic transmission and the learning of spatial information are prevented. The NMDA receptor can bind a protein known as postsynaptic density-95 (PSD-95), which may regulate the localization of and/or signalling by the receptor. In mutant mice lacking PSD-95, the frequency function of NMDA-dependent LTP and LTD is shifted to produce strikingly enhanced LTP at different frequencies of synaptic stimulation. In keeping with neural-network models that incorporate bidirectional learning rules, this frequency shift is accompanied by severely impaired spatial learning. Synaptic NMDA-receptor currents, subunit expression, localization and synaptic morphology are all unaffected in the mutant mice. PSD-95 thus appears to be important in coupling the NMDA receptor to pathways that control bidirectional synaptic plasticity and learning.

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Figure 1: Targeted disruption of the PSD-95 gene.
Figure 2: Anatomy and NR1 localization in hippocampus CA1 region of mice.
Figure 3: NMDA-receptor currents and synaptic physiology.
Figure 6: Model for PSD-95 function.
Figure 4: Frequency-dependent changes in synaptic strength.
Figure 5: Behavioural data.

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Acknowledgements

We thank A. J. H. Smith for advice and for the 129 genomic library, J. Ure for embryo injection, L. Anderson and J. Young for mouse care, W. Janssen for technical assistance, F. Johnston and G.Brown for photography, and R. Ellaway for illustrations. This work was supported by the Fyssen Foundation (M.M.) and the BBSRC (M.M., M.D. and P.C.), by grants from the NIH and the Charles A. Dana Foundation (J.H.M. and Y.H.), the Esther A. and Joseph Klingenstein Fund and the Pew Charitable Trusts (T.J.O.), a grant from the National Institute of Mental Health (T.J.O.), and the Wellcome Trust (L.C.W. and S.G.N.G.).

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Authors and Affiliations

  1. Centre for Genome Research, and Centre for Neuroscience, University of Edinburgh, Roger Land Building, West Mains Road, EH9 3JQ, Edinburgh, UK

    Martine Migaud, Paul Charlesworth, Maureen Dempster, Lorna C. Webster & Seth G. N. Grant

  2. Centre for Neuroscience, University of Edinburgh, Roger Land Building, West Mains Road, EH9 3JQ, Edinburgh, UK

    Martine Migaud, Paul Charlesworth, Maureen Dempster, Lorna C. Webster, Mark F. Ramsay, Richard G. M. Morris & Seth G. N. Grant

  3. Department of Physiology and The Brain Research Institute, School of Medicine, University of California at Los Angeles, Los Angeles, 90095, California, USA

    Ayako M. Watabe, Michael Makhinson & Thomas J. O'Dell

  4. Fishberg Research Centre for Neurobiology, Mount Sinai School of Medicine, Box 1065, One Gustave Levy Place, New York, 10029-6574, New York, USA

    Yong He & John H. Morrison

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  1. Martine Migaud
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Correspondence to Seth G. N. Grant.

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Migaud, M., Charlesworth, P., Dempster, M. et al. Enhanced long-term potentiation and impaired learning in mice with mutant postsynaptic density-95 protein. Nature 396, 433–439 (1998). https://doi.org/10.1038/24790

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