Neuronal effects of progranulin deficiency contribute to frontotemporal dementia independent of neuroinflammation

Frontotemporal dementia (FTD) is a fatal neurodegenerative disease characterized by changes in social and emotional behavior. The disease can be caused by mutations in GRN that result in haploinsufficiency of the neuronal and microglial protein progranulin. Recent findings using Grn-/- mice have directed attention to progranulin's function in microglia and its contribution to neuroinflammation. Grn-/- mice have FTD-related behavioral deficits and gliosis similar to the human disease, however they do not model progranulin haploinsufficiency. We sought to determine the relative effects of progranulin insufficiency on neurons and microglia in mouse models. In this study we tested the behavior, physiology, neuropathology, inflammatory mediators, and neuronal morphology in Grn+/- mice at different ages to investigate the relationship between neuroinflammation and neuronal dysfunction in FTD. Grn+/- mice displayed FTD-related behavioral deficits, similar to Grn-/- mice, without neuroinflammation. We found reduced social behavior in Grn+/- and Grn-/- mice using the three-chamber sociability test. This social deficit was constant between multiple cohorts on two separate genetic backgrounds and appeared to be age-dependent, with deficits emerging after 4 months. In addition to the three-chamber test, we observed abnormal social behavior in Grn+/- mice using the tube test of social dominance. We also found emotional impairments in Grn+/- and Grn-/- mice, evident by decreased freezing in a classical fear-condition paradigm. Whereas social/emotion impairment was clear, we found no hippocampal-dependent behavioral or electrophysiological impairment in Grn+/- mice. This is consistent with the relative preservation of other cognitive domains early in FTD.Gliosis and increased TNF-Î ± mRNA levels were not observed in Grn+/- mice, unlike Grn-/- mice, demonstrating a dissociation of neuroinflammation and neuronal dysfunction. Therefore, we analyzed neuronal morphology and found that Grn+/- mice, as well as Grn-/- mice, displayed abnormal dendritic architecture in the amygdala, a region that controls social/emotional behavior and is implicated in FTD. Our results demonstrate that neuroinflammation and microglial involvement are not a driving force in FTD due to progranulin haploinsufficiency and suggest a vital role for progranulin in neurons. Also, Grn+/- mice are a useful tool in studying the behavioral deficits in FTD.