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

Rui M. Costa, Nikolai B. Federov, Jeff H. Kogan, Geoffrey G. Murphy, Joel Stern, Masuo Ohno, Raju Kucherlapati, Tyler Jacks and Alcino J. Silva ()
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Rui M. Costa: Psychiatry and Psychology, BRI, University of California at Los Angeles
Nikolai B. Federov: Psychiatry and Psychology, BRI, University of California at Los Angeles
Jeff H. Kogan: Psychiatry and Psychology, BRI, University of California at Los Angeles
Geoffrey G. Murphy: Psychiatry and Psychology, BRI, University of California at Los Angeles
Joel Stern: Psychiatry and Psychology, BRI, University of California at Los Angeles
Masuo Ohno: Psychiatry and Psychology, BRI, University of California at Los Angeles
Raju Kucherlapati: Albert Einstein College of Medicine
Tyler Jacks: Massachusetts Institute of Technology
Alcino J. Silva: Psychiatry and Psychology, BRI, University of California at Los Angeles

Nature, 2002, vol. 415, issue 6871, 526-530

Abstract: 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.

Date: 2002
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DOI: 10.1038/nature711

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