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Mechanism for the learning deficits in a mouse model of neurofibromatosis type 1

Nature volume 415, pages 526–530 (2002)Cite this article

Abstract

Neurofibromatosis type I (NF1) is one of the most common single-gene disorders that causes learning deficits in humans1. Mice carrying a heterozygous null mutation of the Nf1 gene (Nf1+/−) show important features of the learning deficits associated with NF1 (ref. 2). Although neurofibromin has several known properties and functions, including Ras GTPase-activating protein activity3,4, adenylyl cyclase modulation5,6 and microtubule binding7, it is unclear which of these are essential for learning in mice and humans. Here we show that the learning deficits of Nf1+/− mice can be rescued by genetic and pharmacological manipulations that decrease Ras function. We also show that the Nf1+/− mice have increased GABA (γ-amino butyric acid)-mediated inhibition and specific deficits in long-term potentiation, both of which can be reversed by decreasing Ras function. Our results indicate that the learning deficits associated with NF1 may be caused by excessive Ras activity, which leads to impairments in long-term potentiation caused by increased GABA-mediated inhibition. Our findings have implications for the development of treatments for learning deficits associated with NF1.

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Figure 1: Learning deficits of Nf1+/− mice are Ras dependent.
Figure 2: Ras-dependent long-term potentiation deficits in Nf1+/− animals.
Figure 3: Ras-dependent enhanced inhibition in Nf1+/− mice.
Figure 4: Long-term potentiation deficits in Nf1+/− mice are caused by increased inhibition.

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Acknowledgements

We thank V. Manne for the BMS191563, and E. Friedman for technical assistance in earlier experiments. We are grateful to M. Barad, D. Buonomano, T. Cannon, J. Colicelli, P. Frankland, L. Kaczmarek, A. Matynia, M. Sanders and D. Smith for discussions, and to C. Brannan and S. Schlussel for encouragement. R.M.C. received support from the Graduated Program in Basic and Applied Biology (GABBA) of the University of Oporto, the Portuguese Foundation for Science and Technology (FCT) and the National Neurofibromatosis Foundation (NNF). This work was also supported by a generous donation from K. M. Spivak, and by grants from the NIH, Neurofibromatosis Inc. (National, Illinois, Mass Bay Area, Minnesota, Arizona, Kansas and Central Plains, Mid-Atlantic, and Texas chapters), the Merck and the NNF foundations to A.J.S.

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Author notes

  1. Tyler Jacks

    Present address: Department of Biology, Massachusetts Institute of Technology, Cambridge, 02139, Massachusetts, USA

  2. Nikolai B. Federov & Jeff H. Kogan

    Present address: Memory Pharmaceuticals Corporation, 100 Philips Parkway, Montvale, New Jersey, 07645, USA

Authors and Affiliations

  1. Departments of Neurobiology, Psychiatry and Psychology, BRI, University of California at Los Angeles, Los Angeles, California, 90095-1761, USA

    Rui M. Costa, Nikolai B. Federov, Jeff H. Kogan, Geoffrey G. Murphy, Joel Stern, Masuo Ohno & Alcino J. Silva

  2. Department of Molecular Genetics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York, 10461, New York, USA

    Raju Kucherlapati

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Correspondence to Alcino J. Silva.

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Costa, R., Federov, N., Kogan, J. et al. Mechanism for the learning deficits in a mouse model of neurofibromatosis type 1. Nature 415, 526–530 (2002). https://doi.org/10.1038/nature711

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