Microglial NFκB-TNFα hyperactivation induces obsessive–compulsive behavior in mouse models of progranulin-deficient frontotemporal dementia

Abstract

Frontotemporal dementia (FTD) is the second most common dementia before 65 years of age. Haploinsufficiency in the progranulin (GRN) gene accounts for 10% of all cases of familial FTD. GRN 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 GRN mutations and in mice lacking progranulin (PGRN). We found that patients and mice with GRN 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.

A critical role of TRPM2 channel in Aβ42‐induced microglial activation and generation of tumor necrosis factor‐α

“…Treatment with 1 lM PF, a PYK2 inhibitor, or 3 lM U0126, a MEK/ERK inhibitor, largely prevented Ab 42 -induced microglial activation (Figure 8a,b). As introduced above, it has been welldocumented that TNF-a is potent in inducing neurotoxicity and that Ab-induced generation of TNF-a from microglial cells significantly contributes to neuroinflammation in AD (Alam et al, 2016;Block et al, 2007;Doll et al, 2015;Heppner et al, 2015;Krabbe et al, 2017;Liu & Hong, 2003;Montgomery et al, 2011;Montgomery et al, 2013;Wyss-Coray & Rogers, 2012). Treatment with 1 lM PF or 3 lM U0126 strongly inhibited Ab 42 -induced activation of PARP-1 (Figure 9a It has been well recognized that Ab causes neuroinflammation via inducing microglial activation and generation of excessive proinflammatory cytokines, thereby contributing to AD (Heneka et al, 2015;Heppner et al, 2015).…”

“…(g) Summary of TNF-a release determined by ELISA from microglial cells after exposed to Ab 42 at indicated concentrations for 72 hr from four independent cell preparations. TNF-a is a major neurotoxic cytokine generated by microglial cells (Block, Zecca, & Hong, 2007;Doll, Rellick, Barr, Ren, & Simpkins, 2015;Heppner et al, 2015;Krabbe et al, 2017;Sedger & McDermott, 2014). *p < .05; **p < .01; ***p < .005 compared with control [Color figure can be viewed at wileyonlinelibrary.com] ALAWIEYAH SYED MORTADZA ET AL.…”

The immune system and psychiatric disease: a basic science perspective

“…Several studies in mouse suggest that microglia may directly affect behavior. For example, absence of homeobox protein Hox‐B8 (Hoxb8) or progranulin in microglia leads to obsessive–compulsive disorder (OCD)‐like symptoms in rodents, such as excessive grooming , while absence of Cx3cr1 leads to ASD‐like symptoms . A recent study also observed a sex‐specific role for microglial phagocytosis in male social play , setting the stage for further study of molecular mechanisms by which microglia cause psychiatric symptoms.…”

Review: Modelling the pathology and behaviour of frontotemporal dementia

“…Heterozygous Grn knockout mice also present with milder social deficits, but still include reduced sociability . Homozygous knockout mice also show marked gliosis and inflammatory markers in the brain, and interfering with inflammatory pathways rescues several behavioural impairments and improves survival in these mice . Depending on the extent of knockdown (and potentially other factors), selective knockdown of progranulin in microglia is also sufficient to induce social grooming impairments and compulsive behaviour in mice .…”

“…Homozygous knockout mice also show marked gliosis and inflammatory markers in the brain, and interfering with inflammatory pathways rescues several behavioural impairments and improves survival in these mice . Depending on the extent of knockdown (and potentially other factors), selective knockdown of progranulin in microglia is also sufficient to induce social grooming impairments and compulsive behaviour in mice . However, behavioural abnormalities in heterozygous Grn knockout mice and neuronal‐specific knockout occur without concomitant microgliosis or neuroinflammation , suggesting that they are not essential for the development of these phenotypes.…”