Progranulin haploinsufficiency causes biphasic social dominance abnormalities in the tube test

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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.

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