title: 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, 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.
authors.affiliation: Center for Neurodegeneration and Experimental Therapeutics, Alzheimer's Disease Center, Evelyn F. McKnight Brain Institute, Departments of Neurology and Neurobiology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: A E
authors.identifier: 0000-0003-4706-9411
authors.initials: AE
authors.lastname: Arrant
authors.affiliation: Center for Neurodegeneration and Experimental Therapeutics, Alzheimer's Disease Center, Evelyn F. McKnight Brain Institute, Departments of Neurology and Neurobiology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: A J
authors.initials: AJ
authors.lastname: Filiano
authors.affiliation: Center for Neurodegeneration and Experimental Therapeutics, Alzheimer's Disease Center, Evelyn F. McKnight Brain Institute, Departments of Neurology and Neurobiology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: B A
authors.initials: BA
authors.lastname: Warmus
authors.affiliation: Center for Neurodegeneration and Experimental Therapeutics, Alzheimer's Disease Center, Evelyn F. McKnight Brain Institute, Departments of Neurology and Neurobiology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Hall
authors.affiliation: Center for Neurodegeneration and Experimental Therapeutics, Alzheimer's Disease Center, Evelyn F. McKnight Brain Institute, Departments of Neurology and Neurobiology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: E D
authors.initials: ED
authors.lastname: Roberson
mesh_terms: D000679:Amygdala / Q000254:growth & development / Q000378:metabolism; D000818:Animals; D005260:Female; D000077155:Granulins; D057895:Haploinsufficiency; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D008810:Mice, Inbred C57BL; D046912:Multiprotein Complexes / Q000378:metabolism; D055495:Neurogenesis; D017397:Prefrontal Cortex / Q000254:growth & development / Q000378:metabolism; D000077153:Progranulins; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D012930:Social Dominance; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D000077155:Granulins; C120204:Grn protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D046912:Multiprotein Complexes; D000077153:Progranulins; D000076225:Mechanistic Target of Rapamycin Complex 2; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases
keywords: Aging; behavior; dominance; frontotemporal dementia; haploinsufficiency; neurodegeneration; preclinical; progranulin; social; tube test