title: Repetitive grooming and sensorimotor abnormalities in an ephrin-A knockout model for Autism Spectrum Disorders.
abstract: EphA receptors and ephrin-A ligands play important roles in neural development and synaptic plasticity in brain regions where expression persists into adulthood. Recently, EPHA3 and EPHA7 gene mutations were linked with Autism Spectrum Disorders (ASDs) and developmental neurological delays, respectively. Furthermore, deletions of ephrin-A2 or ephrin-A3, which exhibit high binding affinity for EphA3 and EphA7 receptors, are associated with subtle deficits in learning and memory behavior and abnormalities in dendritic spine morphology in the cortex and hippocampus in mice. To better characterize a potential role for these ligands in ASDs, we performed a comprehensive behavioral characterization of anxiety-like, sensorimotor, learning, and social behaviors in ephrin-A2/-A3 double knockout (DKO) mice. The predominant phenotype in DKO mice was repetitive and self-injurious grooming behaviors such as have been associated with corticostriatal circuit abnormalities in other rodent models of neuropsychiatric disorders. Consistent with ASDs specifically, DKO mice exhibited decreased preference for social interaction in the social approach assay, decreased locomotor activity in the open field, increased prepulse inhibition of acoustic startle, and a shift towards self-directed activity (e.g., grooming) in novel environments, such as marble burying. Although there were no gross deficits in cognitive assays, subtle differences in performance on fear conditioning and in the Morris water maze resembled traits observed in other rodent models of ASD. We therefore conclude that ephrin-A2/-A3 DKO mice have utility as a novel ASD model with an emphasis on sensory abnormalities and restricted, repetitive behavioral symptoms.
authors.affiliation: Georgetown University, Department of Neuroscience, Washington, DC 20057, United States of America; Georgetown University, Interdisciplinary Program in Neuroscience, Washington, DC 20057, United States of America; Georgetown University, Department of Pharmacology and Physiology, Washington, DC 20057, United States of America. Electronic address: rpw9@georgetown.edu.
authors.forename: Rachel
authors.initials: R
authors.lastname: Wurzman
authors.affiliation: Georgetown University, Interdisciplinary Program in Neuroscience, Washington, DC 20057, United States of America; Georgetown University, Department of Pharmacology and Physiology, Washington, DC 20057, United States of America.
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Forcelli
authors.affiliation: Georgetown University, Department of Biology, Washington, DC 20057, United States of America.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Griffey
authors.affiliation: Georgetown University, Department of Neuroscience, Washington, DC 20057, United States of America; Georgetown University, Interdisciplinary Program in Neuroscience, Washington, DC 20057, United States of America.
authors.forename: Lawrence F
authors.initials: LF
authors.lastname: Kromer
mesh_terms: D000818:Animals; D000067877:Autism Spectrum Disorder / Q000150:complications* / Q000235:genetics*; D003213:Conditioning, Psychological / Q000502:physiology; D004195:Disease Models, Animal; D036383:Ephrin-A2 / Q000172:deficiency* / Q000235:genetics; D036384:Ephrin-A3 / Q000172:deficiency* / Q000235:genetics; D005106:Exploratory Behavior / Q000502:physiology; D005239:Fear / Q000502:physiology; D020233:Gait Disorders, Neurologic / Q000209:etiology*; D006120:Grooming / Q000502:physiology*; D007398:Interpersonal Relations; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000235:genetics; D065808:Prepulse Inhibition / Q000235:genetics; D013216:Reflex, Startle / Q000235:genetics; D013239:Stereotyped Behavior / Q000502:physiology*
chemical_list: D036383:Ephrin-A2; D036384:Ephrin-A3
keywords: ASD mouse model; Autism spectrum disorder; Behavior; Ephrin-A; Grooming