Title | Microglial NFκB-TNFα hyperactivation induces obsessive-compulsive behavior in mouse models of progranulin-deficient frontotemporal dementia. |
Publication Type | Journal Article |
Year of Publication | 2017 |
Authors | Krabbe G, S Minami S, Etchegaray JI, Taneja P, Djukic B, Davalos D, Le D, Lo I, Zhan L, Reichert MC, Sayed F, Merlini M, Ward ME, Perry DC, Lee SE, Sias A, Parkhurst CN, Gan W-B, Akassoglou K, Miller BL, Farese RV, Gan L |
Journal | Proc Natl Acad Sci U S A |
Volume | 114 |
Issue | 19 |
Pagination | 5029-5034 |
Date Published | 2017 05 09 |
ISSN | 1091-6490 |
Keywords | Aged, Aged, 80 and over, Animals, Disease Models, Animal, Female, Frontotemporal Dementia, Humans, Intercellular Signaling Peptides and Proteins, Male, Mice, Mice, Knockout, Microglia, NF-kappa B, Obsessive-Compulsive Disorder, Tumor Necrosis Factor-alpha |
Abstract | Frontotemporal dementia (FTD) is the second most common dementia before 65 years of age. Haploinsufficiency in the progranulin () gene accounts for 10% of all cases of familial FTD. mutation carriers have an increased risk of autoimmune disorders, accompanied by elevated levels of tissue necrosis factor (TNF) α. We examined behavioral alterations related to obsessive-compulsive disorder (OCD) and the role of TNFα and related signaling pathways in FTD patients with mutations and in mice lacking progranulin (PGRN). We found that patients and mice with mutations displayed OCD and self-grooming (an OCD-like behavior in mice), respectively. Furthermore, medium spiny neurons in the nucleus accumbens, an area implicated in development of OCD, display hyperexcitability in PGRN knockout mice. Reducing levels of TNFα in PGRN knockout mice abolished excessive self-grooming and the associated hyperexcitability of medium spiny neurons of the nucleus accumbens. In the brain, PGRN is highly expressed in microglia, which are a major source of TNFα. We therefore deleted PGRN specifically in microglia and found that it was sufficient to induce excessive grooming. Importantly, excessive grooming in these mice was prevented by inactivating nuclear factor κB (NF-κB) in microglia/myeloid cells. Our findings suggest that PGRN deficiency leads to excessive NF-κB activation in microglia and elevated TNFα signaling, which in turn lead to hyperexcitability of medium spiny neurons and OCD-like behavior. |
DOI | 10.1073/pnas.1700477114 |
Alternate Journal | Proc. Natl. Acad. Sci. U.S.A. |
PubMed ID | 28438992 |
PubMed Central ID | PMC5441749 |
Grant List | K23 AG045289 / AG / NIA NIH HHS / United States P50 AG023501 / AG / NIA NIH HHS / United States R01 AG036884 / AG / NIA NIH HHS / United States R35 NS097976 / NS / NINDS NIH HHS / United States P30 NS065780 / NS / NINDS NIH HHS / United States F32 NS076239 / NS / NINDS NIH HHS / United States P01 AG019724 / AG / NIA NIH HHS / United States K23 AG039414 / AG / NIA NIH HHS / United States R01 AG051390 / AG / NIA NIH HHS / United States R01 NS087198 / NS / NINDS NIH HHS / United States |