Progranulin Haploinsufficiency Causes Biphasic Social Dominance Abnormalities in the Tube Test

Genes Brain Behav. 2016 Jul;15(6):588-603. doi: 10.1111/gbb.12300.

Abstract

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.

Keywords: Aging; behavior; dominance; frontotemporal dementia; haploinsufficiency; neurodegeneration; preclinical; progranulin; social; tube test.

MeSH terms

  • Amygdala / growth & development
  • Amygdala / metabolism
  • Animals
  • Female
  • Granulins
  • Haploinsufficiency
  • Intercellular Signaling Peptides and Proteins / genetics*
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Male
  • Mechanistic Target of Rapamycin Complex 2
  • Mice
  • Mice, Inbred C57BL
  • Multiprotein Complexes / metabolism
  • Neurogenesis
  • Prefrontal Cortex / growth & development
  • Prefrontal Cortex / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction
  • Social Dominance*
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • Granulins
  • Grn protein, mouse
  • Intercellular Signaling Peptides and Proteins
  • Multiprotein Complexes
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 2
  • Proto-Oncogene Proteins c-akt