TitleMicroglial NFκB-TNFα hyperactivation induces obsessive-compulsive behavior in mouse models of progranulin-deficient frontotemporal dementia.
Publication TypeJournal Article
Year of Publication2017
AuthorsKrabbe 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
JournalProc Natl Acad Sci U S A
Volume114
Issue19
Pagination5029-5034
Date Published2017 05 09
ISSN1091-6490
KeywordsAged, 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.

DOI10.1073/pnas.1700477114
Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID28438992
PubMed Central IDPMC5441749
Grant ListK23 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