Cognitive dysfunction in NF1 knock-out mice may result from altered vesicular trafficking of APP/DRD3 complex

To elucidate genes involved in the pathogenic process, gene expression analysis was performed comparing the expression profiles in various brain regions for control and Nf1+/- heterozygous mice. Gene expression analysis was performed for hippocampal samples dissected from postnatal day 10, 15, and 20 mice utilizing the Affymetrix Mouse Genome chip (Murine 430 2.0). Analysis of expression profiles between Nf1+/-and wild-type animals was focused on the hippocampus because of previous studies demonstrating alterations in hippocampal LTP in the Nf1+/- mice, and the region's importance in visual/spatial learning. Network analysis identified links between neurofibromin and kinesin genes, which were down regulated in the Nf1+/- mice at postnatal days 15 and 20.Through this analysis, it is proposed that neurofibromin forms a binding complex with amyloid precursor protein (APP) and through filamin proteins interacts with a dopamine receptor (Drd3). Though the effects of these interactions are not yet known, this information may provide novel ideas about the pathogenesis of cognitive defects in NF1 and may facilitate the development of novel targeted therapeutic interventions.Neurofibromatosis type 1 (also known as von Recklinghausen disease) is an autosomal dominant disorder with a prevalence of 1 in 3500, and is characterized by hyperpigmented skin macules (café au lait spots), iris tumors (Lisch nodules), and benign tumors of nerve cells (neurofibromas) [1]. Other physical complications observed in NF1 patients include optic pathway gliomas, scoliosis, macrocephaly, epilepsy, chronic headaches, bending of the long bones (pseudoarthrosis), and sphenoid wing dysplasia [2]. Cognitive deficits in spatial learning and memory also accompany these more physical manifestations of NF1 [3]. Though mental retardation is not commonly seen in NF1 patients, a high proportion of children afflicted with NF1 show learning disabilities (30 – 65%) [3]. These children perform poorly on tasks