Neurofibromatosis 1 (NF1) is a common single-gene disorder that causes learning impairments in patients. Neurofibromin encoded by the NF1 causal gene regulates Ras/MAPK and cAMP signaling pathways. These signaling pathways play critical roles in controlling gene transcription during synaptic plasticity and memory formation. We hypothesized that NF1 mutations disturb the expression of genes important for memory formation. To test this hypothesis, we performed DNA microarray analysis on the hippocampus of NF1(+/-) mice, the mouse model for NF1 learning disabilities. Our results indicated that genes involved in a wide spectrum of biological processes are dysregulated in the NF1(+/-) hippocampus. Many of the NF1-affected genes play critical roles in synaptic plasticity, such as Rabs, synaptotagmins, NMDAR1, CaMKII, and CREB1. Because NF1-associated learning disabilities can be reversed by lovastatin, we also determined the effect of lovastatin treatment on genome-wide expression patterns of the NF1(+/-) hippocampus. We found that lovastatin altered the expression of a large number of genes, including those disturbed by NF1 mutations. Our results reveal a genome-wide overview of the molecular abnormalities in the NF1(+/-) hippocampus and should be useful for further identifying the novel molecular pathways that cause NF1 learning deficits.
(c) 2009 Wiley-Liss, Inc.