title: Genetic inhibition of Anaplastic Lymphoma Kinase rescues cognitive impairments in Neurofibromatosis 1 mutant mice.
abstract: Heterozygous Neurofibromatosis 1 (NF1) loss of function mutations occur in approximately 90% of patients with neurofibromatosis. A major, disabling phenotypic consequence of reduced NF1 function is cognitive impairment; a possibly related behavioral phenotype is impaired sleep. Recent results in Drosophila have demonstrated a genetic interaction between Anaplastic Lymphoma Kinase (Alk) and NF1 for both associative learning and sleep. Inhibition of Alk improves associative learning and sleep in heterozygous NF1 mutant flies. The results in Drosophila provide a strong motivation to investigate NF1/Alk genetic interactions in mice. In Drosophila, activation of Alk by its ligand, Jelly belly (Jeb), is the physiologically relevant target of negative regulation by NF1. Therefore, we tested whether genetic inhibition of Alk in heterozygous NF1 mutant mice attenuates or rescues cognitive impairments in mice. Our results are consistent with the hypothesis that NF1 functions in mice biochemically to inhibit signaling from Alk through Ras. The cognitive phenotypes observed in heterozygous NF1 mutant mice are rescued or ameliorated by genetic inhibition of Alk activity. In two tests of hippocampus-dependent learning, the Morris water maze and extinction of contextual fear, mutation of one or both alleles of Alk was sufficient to improve performance to wild type or near wild type levels in NF1-/+ mice. In addition, in NF1 mice genetic inhibition of Alk improves circadian activity levels. These data are intriguing in light of the circadian alterations seen in NF1 patients and indicate that inhibition of Alk activity may cognitively benefit patients with Neurofibromatosis 1.
authors.affiliation: Cardiovascular Institute and Warren Alpert School of Medicine at Brown University Providence, RI 02840, USA.
authors.forename: Joseph B
authors.initials: JB
authors.lastname: Weiss
authors.affiliation: Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: Sydney J
authors.initials: SJ
authors.lastname: Weber
authors.affiliation: Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: Eileen Ruth S
authors.initials: ERS
authors.lastname: Torres
authors.affiliation: Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: Tessa
authors.initials: T
authors.lastname: Marzulla
authors.affiliation: Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR 97239, USA; Departments of Neurology, and Radiation Medicine, Division of Neuroscience, ONPRC, Oregon Health & Science University, Portland, OR 97239, USA. Electronic address: raberj@ohsu.edu.
authors.forename: Jacob
authors.initials: J
authors.lastname: Raber
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D002940:Circadian Rhythm / Q000502:physiology; D060825:Cognitive Dysfunction / Q000201:enzymology* / Q000209:etiology / Q000628:therapy*; D003213:Conditioning, Psychological / Q000502:physiology; D005108:Extinction, Psychological / Q000502:physiology; D005239:Fear / Q000502:physiology; D005260:Female; D008297:Male; D018782:Maze Learning / Q000502:physiology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D009456:Neurofibromatosis 1 / Q000150:complications / Q000201:enzymology* / Q000523:psychology*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D065852:Spatial Memory / Q000502:physiology
chemical_list: C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases
keywords: Alk; Cognition; Hippocampus; NF1; Neurofibromatosis