1. Departments of Neurobiology, Psychiatry and Psychology, BRI, University of California at Los Angeles, Los Angeles, California 90095-1761, USA
2. Department of Molecular Genetics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York, New York 10461, USA
3. Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
4. Present address: Memory Pharmaceuticals Corporation, 100 Philips Parkway, Montvale, New Jersey 07645, USA

Correspondence to: Alcino J. Silva¹ Correspondence and requests for materials should be addressed to A.J.S. (e-mail: Email: Silvaa@mednet.ucla.edu)

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 activity^{3, 4}, adenylyl cyclase modulation^{5, 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 (-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.