Dissertation/Thesis Abstract

Novel cognitive impairments identified in a Drosophila model of Neurofibromatosis Type 1
by Vose, Linnea Raeanne, Ph.D., New York Medical College, 2012, 135; 3558249
Abstract (Summary)

Neurofibromatosis Type 1 (NF1) is a common genetic disorder. Besides physical abnormalities, up to 60% of children with NF1 exhibit cognitive problems including learning defects, attention deficit hyperactivity disorder, and difficulty with visuo-spatial tasks, e.g. judgment of line orientation (JLO). Animal models with mutations in the neurofibromin (NF1) gene also show cognitive deficits. Two NF1-dependent intracellular pathways regulate learning and long term memory (LTM) in flies. The carboxy terminus of the NF1 protein stimulates an adenylyl cyclase (AC) that raises cAMP levels and protein kinase A (PKA) activity required for learning. The central GAP domain of NF1 deactivates Ras to decrease activity in downstream mitogen activated protein kinase (MAPK) and phosphoinositide-3 kinase (PI3K) pathways required for LTM. Pharmacological inhibitors exist for these pathways, including some drugs approved for use in humans for other indications. We hypothesize that compounds targeting the AC/PKA or MAPK/PI3K pathways will have modulating effects on cognitive ability, specifically learning and/or attention. In this study, three FDA approved compounds, lovastatin, rolipram, and rapamycin, were each fed to flies overnight before behavioral testing in one of three cognitive assessment assays. We developed a simplified olfactory learning apparatus, and a flight simulator with a novel collection of components.

Olfactory learning is a common and robust learning assay used for Drosophila. Visual learning and attention were assayed using a flight simulator containing visual cues. Effects of the drugs were also monitored at the biochemical level. Drosophila NF1 mutants are known to have impaired olfactory learning but we are the first to test for defects in visual learning or attention-like behavior. These studies are the first to identify deficits in visual learning and attention-like behavior in NF1 mutant flies. Treatment with these drugs did not change the behavior or biochemical markers of NF1 mutants. The visual learning ability of control flies was impaired after treatment, indicating that the drugs were able to affect relevant cognitive pathways. Future studies of Drosophila learning and attention-like behavior should facilitate the identification of novel therapeutics for humans suffering from NF1-associated cognitive deficits.

Indexing (document details)
Advisor: Hannan, Frances, Stanton, Patric K.
Commitee: Fried, Victor, Olson, Susan, Pfleger, Cathie
School: New York Medical College
Department: Cell Biology
School Location: United States -- New York
Source: DAI-B 74/08(E), Dissertation Abstracts International
Source Type: DISSERTATION
Subjects: Neurosciences, Pharmacology, Behavioral Sciences, Cognitive psychology
Keywords: Attention, Behavior, Cognitive impairments, Learning deficits, Neurofibromatosis Type 1, Olfactory, Visual
Publication Number: 3558249
ISBN: 9781303026218
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