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Memory deficits, gait ataxia and neuronal loss in the hippocampus and cerebellum in mice that are heterozygous for Pur-alpha.

Neuroscience. 2016 Nov 19;337:177-190. Epub 2016 Sep 17
Mary F Barbe 1 , Jessica J Krueger 2 , Regina Loomis 2 , Jessica Otte 3 , Jennifer Gordon 3
Mary F Barbe 1 , Jessica J Krueger 2 , Regina Loomis 2 , Jessica Otte 3 , Jennifer Gordon 3

[No authors listed]

Author information
  • 1 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.
  • 2 Comprehensive NeuroAIDS Center, Temple University School of Medicine, Philadelphia, PA, USA.
  • 3 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.

摘要


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.

KEYWORDS: PURA, animals, brain pathology, knockout, mice, puralpha