Progranulin haploinsufficiency causes biphasic social dominance abnormalities in the tube test

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, though 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 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 demonstrate a progressive change in tube test dominance in Grn ^+/− mice and show that partial, but not complete progranulin deficiency disrupts this behavior in mice.