Progranulin haploinsufficiency causes biphasic social dominance abnormalities in the tube test

Academic Article

Abstract

  • © 2016 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society. Loss-of-function mutations in progranulin (GRN) are a major autosomal dominant cause of frontotemporal dementia (FTD), a neurodegenerative disorder in which social behavior is disrupted. Progranulin-insufficient mice, both Grn+/- and Grn-/-, are used as models of FTD due to GRN mutations, with Grn+/- mice mimicking the progranulin haploinsufficiency of FTD patients with GRN mutations. Grn+/- mice have increased social dominance in the tube test at 6 months of age, although this phenotype has not been reported in Grn-/- mice. In this study, we investigated how the tube test phenotype of progranulin-insufficient mice changes with age, determined its robustness under several testing conditions, and explored the associated cellular mechanisms. We observed biphasic social dominance abnormalities in Grn+/- mice: at 6–8 months, Grn+/- mice were more dominant than wild-type littermates, while after 9 months of age, Grn+/- mice were less dominant. In contrast, Grn-/- mice did not exhibit abnormal social dominance, suggesting that progranulin haploinsufficiency has distinct effects from complete progranulin deficiency. The biphasic tube test phenotype of Grn+/- mice was associated with abnormal cellular signaling and neuronal morphology in the amygdala and prefrontal cortex. At 6–9 months, Grn+/- mice exhibited increased mTORC2/Akt signaling in the amygdala and enhanced dendritic arbors in the basomedial amygdala, and at 9–16 months Grn+/- mice exhibited diminished basal dendritic arbors in the prelimbic cortex. These data show a progressive change in tube test dominance in Grn+/- mice and highlight potential underlying mechanisms by which progranulin insufficiency may disrupt social behavior.
  • Digital Object Identifier (doi)

    Author List

  • Arrant AE; Filiano AJ; Warmus BA; Hall AM; Roberson ED
  • Start Page

  • 588
  • End Page

  • 603
  • Volume

  • 15
  • Issue

  • 6