CHAPTER 3 - Molecular and Cellular Mechanisms of Learning Disabilities: A Focus on Neurofibromatosis Type I

Abstract

Learning Disabilities (LD) affect approximately 15% of the US population, but currently there are no generally effective therapies for this class of cognitive disorders. To address this problem, it has been initially focused on Neurofibromatosis type I (NF1), a single gene disorder associated with learning disabilities. Previous studies showed that mice with a heterozygous null mutation of the NF1 gene have behavioral deficits related to the cognitive phenotype of NF1 patients. Studies of these mice showed increased Ras/MAPK signaling in the hippocampus and prefrontal cortex, which results in the upregulation of GABA release underlying the spatial, attention and working memory deficits of the mutants. Statins can be used to decrease the isoprenylation; therefore, the activity of Ras. Recent results demonstrate that a short treatment with statins, which is ineffective in controls, can reverse the increases in Ras-MAPK signaling, the synaptic plasticity, attention, and spatial learning deficits of the NF1 mutant mice. To test whether statins can also reverse the neurological and cognitive deficits associated with NF1 in patients, a series of collaborative pilot clinical studies in children and adults with NF1 has been initiated. These studies will not only have an impact on the understanding of cognitive deficits associated with NF1, it will also serve as a case study for how to investigate and treat learning disabilities.