Letter | Published:

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

Nature volume 415, pages 526530 (31 January 2002) | Download Citation



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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  1. 1.

    Neurofibromatosis type 1. Am. J. Med. Genet. 97, 119–127 (2000)

  2. 2.

    et al. A mouse model for the learning and memory deficits associated with neurofibromatosis type I. Nature Genet. 15, 281–284 (1997)

  3. 3.

    et al. The NF1 locus encodes a protein functionally related to mammalian GAP and yeast IRA proteins. Cell 63, 851–859 (1990)

  4. 4.

    et al. The catalytic domain of the neurofibromatosis type 1 gene product stimulates ras GTPase and complements ira mutants of S. cerevisiae. Cell 63, 835–841 (1990)

  5. 5.

    , , , & Requirement of Drosophila NF1 for activation of adenylyl cyclase by PACAP38-like neuropeptides. Science 276, 795–798 (1997)

  6. 6.

    , , , & A neurofibromatosis-1-regulated pathway is required for learning in Drosophila. Nature 403, 895–898 (2000)

  7. 7.

    & Mutations in the GAP-related domain impair the ability of neurofibromin to associate with microtubules. Brain Res. 759, 149–152 (1997)

  8. 8.

    Cognitive impairment in neurofibromatosis type 1. Am. J. Med. Genet. 89, 45–52 (1999)

  9. 9.

    , , & Place navigation impaired in rats with hippocampal lesions. Nature 297, 681–683 (1982)

  10. 10.

    et al. Learning deficits, but normal development and tumour predisposition, in mice lacking exon 23a of Nf1. Nature Genet. 27, 399–405 (2001)

  11. 11.

    et al. Selective disactivation of neurofibromin GAP activity in neurofibromatosis type 1. Hum. Mol. Genet. 7, 1261–1268 (1998)

  12. 12.

    et al. ras is an essential gene in the mouse with partial functional overlap with N-ras. Genes Dev. 11, 2468–2481 (1997)

  13. 13.

    et al. Targeted disruption of the neurofibromatosis type-1 gene leads to developmental abnormalities in heart and various neural crest-derived tissues. Genes Dev. 8, 1019–1029 (1994)

  14. 14.

    , & The use of the Morris water maze in the study of memory and learning. Int. J. Neurosci. 48, 29–69 (1989)

  15. 15.

    , & Severity of spatial learning impairment in aging: Development of a learning index for performance in the Morris water maze. Behav. Neurosci. 107, 618–626 (1993)

  16. 16.

    et al. Contribution of Ras GTPase/MAP kinase and cytochrome P450 metabolites to deoxycorticosterone-salt-induced hypertension. Hypertension 35, 457–463 (2000)

  17. 17.

    et al. Farnesyltransferase inhibitors versus Ras inhibitors. Curr. Opin. Chem. Biol. 1, 197–203 (1997)

  18. 18.

    et al. Farnesyltransferase inhibitors block the neurofibromatosis type I (NF1) malignant phenotype. Cancer Res. 55, 3569–3575 (1995)

  19. 19.

    , & Nf1-deficient mouse Schwann cells are angiogenic and invasive and can be induced to hyperproliferate: reversion of some phenotypes by an inhibitor of farnesyl protein transferase. Mol. Cell. Biol. 17, 862–872 (1997)

  20. 20.

    & Synaptic plasticity: taming the beast. Nature Neurosci. 3, 1178–1183 (2000)

  21. 21.

    , & Patterned stimulation at the theta frequency is optimal for the induction of hippocampal long-term potentiation. Brain Res. 368, 347–350 (1986)

  22. 22.

    , & The probability of transmitter release at a mammalian central synapse. Nature 366, 569–572 (1993)

  23. 23.

    , & Effects of GABAA inhibition on the expression of long-term potentiation in CA1 pyramidal cells are dependent on tetanization parameters. Hippocampus 8, 289–298 (1998)

  24. 24.

    , , , & A Ras-dependent chloride current activated by adrenocorticotropin in rat adrenal zona glomerulosa cells. Endocrinology 141, 684–692 (2000)

  25. 25.

    Tong, J. et al. NF1-regulated adenylyl cyclase pathway. Soc. Neurosci. Abstr. abstract no. 345.9 (Society for Neuroscience, New Orleans, 2000).

  26. 26.

    et al. Hyperactivation of p21(ras) and the hematopoietic-specific Rho GTPase, Rac2, cooperate to alter the proliferation of neurofibromin-deficient mast cells in vivo and in vitro. J. Exp. Med. 194, 57–69 (2001)

  27. 27.

    et al. Tumour predisposition in mice heterozygous for a targeted mutation in Nf1. Nature Genet. 7, 353–361 (1994)

  28. 28.

    , , & The murine N-ras gene is not essential for growth and development. Proc. Natl Acad. Sci. USA 92, 1709–1713 (1995)

  29. 29.

    , , & Strain and gender differences in the behaviour of mouse lines commonly used in transgenic studies. Physiol. Behav. 72, 271–281 (2001)

  30. 30.

    , & Whole cell recording from neurons in slices of reptilian and mammalian cerebral cortex. J. Neurosci. Methods 30, 203–210 (1989)

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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

    • Nikolai B. Federov
    •  & Jeff H. Kogan

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


  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, New York 10461, USA

    • Raju Kucherlapati
  3. §Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA

    • Tyler Jacks


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The authors declare no competing financial interests.

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Correspondence to Alcino J. Silva.

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