Specific learning disabilities are the most common neurological complication in children with neurofibromatosis type I (NF1), a neurological disorder that affects 1/4000 people worldwide. The inherent complexity of these cognitive deficits, and the complications of pursuing their study in patients, motivated us to study them in mice mutant for the neurofibromin gene (Nf1+/-). Additionally, uncovering the causes for the learning deficits in Nf1 mutant mice will reveal molecular, cellular, and neuroanatomical substrates of learning and memory. It is important to note that in both mice and humans the NF1 mutation is present throughout development. We have recently shown that the Nf1+/- mice are a model for the learning disabilities caused by the mutation of the NF1 gene in humans. Neurofibromin is a GTPase Activating Protein (GAP) thought to down regulate Ras function. Consistent with this, our laboratory recently found that the heterozygous N-ras mutation (N-ras+/-) """"""""cures"""""""" the spatial learning deficits of the Nf1+/-mice, demonstrating that the modulation of Ras signaling is critical for learning and memory.
The specific aims of this proposal are as follows. 1) To characterize the learning/behavioral impairments of the Nf1+/-mutant mice. I propose to expand the behavioral characterization of the Nf1+/-mice, and to determine whether either the N-, K-ras mutations, or increases in AMPA function (the Nf1 mice have decreased AMPA function) can rescue the behavioral impairments of the Nf1/-mutants. 2) To identify the cellular mechanisms responsible for the learning impairments of the Nf1+/- mutant mice. The experiments proposed will test the hypothesis that the learning impairments of the Nf1+/-mice are caused by increased RAS signaling which disrupts synaptic transmission. 3) To derive mice with neural specific and inducible mutations of Nf1. In both mice and humans the NF1 mutation is present throughout development, and therefore studying the causes for the learning deficits in the Nf1+/-mice will further our understanding of the learning impairments that can be associated with NF1 patients. However, to pinpoint where and when the loss of neurofibromin affects learning, we will derive neural specific and inducible mutations of Nf1. The studies proposed here will not only further our understanding of the function of neurofibromin in the brain, but they will also be crucial for finding treatments for the debilitating neurological impairments associated with Neurofibromatosis Type I.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Cognitive Functional Neuroscience Review Committee (CFN)
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Finkelstein, Robert
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University of California Los Angeles
Schools of Medicine
Los Angeles
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Shilyansky, C; Lee, Y S; Silva, A J (2010) Molecular and cellular mechanisms of learning disabilities: a focus on NF1. Annu Rev Neurosci 33:221-43
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