title: Memory deficits, gait ataxia and neuronal loss in the hippocampus and cerebellum in mice that are heterozygous for Pur-alpha.
abstract: Pur-alpha is a highly conserved sequence-specific DNA and RNA binding protein with established roles in DNA replication, RNA translation, cell cycle regulation, and maintenance of neuronal differentiation. Prior studies have shown that mice lacking Pur-alpha (-/-) display decreased neurogenesis and impaired neuronal differentiation. We sought to examine for the first time, the behavioral phenotype and brain histopathology of mice that are heterozygous (+/-) for Pur-alpha. Standardized behavioral phenotyping revealed a decreased escape response to touch, limb and abdominal hypotonia, and gait abnormalities in heterozygous Pur-alpha (+/-) mice, compared to wild-type (+/+) littermates. Footprint pattern analyses showed wider-based steps, increased missteps and more outwardly rotated hindpaws in heterozygous Pur-alpha (+/-) mice, suggestive of cerebellar pathology. The Barnes maze and novel object location testing revealed significant memory deficits in heterozygous Pur-alpha mice, suggestive of hippocampal pathology. Quantitative immunohistochemical assays of the vermal region of the cerebellum and CA1-3 regions of the hippocampus revealed reduced numbers of neurons in general, as well as reduced numbers of Pur-alpha+-immunopositive neurons and dendrites in heterozygous Pur-alpha mice, compared to wild-type littermates. Past studies have implicated mutations in Pur-alpha in several diseases of brain development and neurodegeneration. When combined with these new findings, the Pur-alpha heterozygous knockout mice may provide an animal model to study mechanisms of and treatments for Pur-alpha-related cognitive deficiencies and neuropathology.
authors.affiliation: Department of Anatomy and Cell Biology, Temple University School of Medicine, Philadelphia, PA, USA; Comprehensive NeuroAIDS Center, Temple University School of Medicine, Philadelphia, PA, USA. Electronic address: mary.barbe@temple.edu.
authors.forename: Mary F
authors.initials: MF
authors.lastname: Barbe
authors.affiliation: Comprehensive NeuroAIDS Center, Temple University School of Medicine, Philadelphia, PA, USA.
authors.forename: Jessica J
authors.initials: JJ
authors.lastname: Krueger
authors.affiliation: Comprehensive NeuroAIDS Center, Temple University School of Medicine, Philadelphia, PA, USA.
authors.forename: Regina
authors.initials: R
authors.lastname: Loomis
authors.affiliation: Department of Neuroscience and Center for Neurovirology, Temple University School of Medicine, Philadelphia, PA, USA; Comprehensive NeuroAIDS Center, Temple University School of Medicine, Philadelphia, PA, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Otte
authors.affiliation: Department of Neuroscience and Center for Neurovirology, Temple University School of Medicine, Philadelphia, PA, USA; Comprehensive NeuroAIDS Center, Temple University School of Medicine, Philadelphia, PA, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Gordon
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D001921:Brain / Q000378:metabolism; D002531:Cerebellum / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020234:Gait Ataxia / Q000503:physiopathology*; D006579:Heterozygote; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008569:Memory Disorders / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism / Q000473:pathology*
chemical_list: D004268:DNA-Binding Proteins; D009419:Nerve Tissue Proteins; C121485:Pura protein, mouse
keywords: PURA; animals; brain pathology; knockout; mice; puralpha