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Microglial NFκB-TNFα hyperactivation induces obsessive-compulsive behavior in mouse models of progranulin-deficient
Grietje Krabbe1,2, S Sakura Minami1,2, Jon I Etchegaray1,2
1Gladstone Institute of Neurological Diseases, University of California, San Francisco, CA 94158.
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.
Insights
Progranulin (GRN) gene mutations linked to frontotemporal dementia (FTD) cause obsessive-compulsive disorder (OCD)-like behaviors. Microglial TNFα signaling, driven by NF-κB, underlies these GRN-associated neurological and behavioral changes.
Area of Science:
- Neuroscience
- Genetics
- Immunology
Background:
- Frontotemporal dementia (FTD) is a common presenile dementia.
- Haploinsufficiency of the progranulin (GRN) gene causes familial FTD and is linked to autoimmune disorders and elevated TNFα.
- GRN mutations are implicated in neuroinflammation and behavioral changes.
Purpose of the Study:
- To investigate behavioral alterations, specifically obsessive-compulsive disorder (OCD)-like behaviors, in GRN mutation carriers.
- To explore the role of tumor necrosis factor-alpha (TNFα) and related signaling pathways in FTD associated with GRN mutations.
- To elucidate the mechanism linking PGRN deficiency to neuronal hyperexcitability and OCD-like behaviors.
Main Methods:
- Examined behavioral changes in FTD patients with GRN mutations and in progranulin (PGRN)-deficient mice.
- Assessed neuronal activity in the nucleus accumbens of PGRN knockout mice.
- Investigated the effects of reducing TNFα levels and manipulating NF-κB signaling in PGRN-deficient mice.
- Generated mice with PGRN specifically deleted in microglia to assess its role.
Main Results:
- GRN mutation carriers and PGRN knockout mice exhibited OCD and OCD-like self-grooming behaviors, respectively.
- PGRN deficiency led to hyperexcitability of medium spiny neurons in the nucleus accumbens.
- Reducing TNFα or inactivating microglial NF-κB signaling ameliorated excessive grooming and neuronal hyperexcitability.
- PGRN deficiency in microglia alone was sufficient to induce excessive grooming.
Conclusions:
- PGRN deficiency triggers excessive NF-κB activation in microglia, leading to elevated TNFα signaling.
- This inflammatory cascade results in medium spiny neuron hyperexcitability and OCD-like behaviors.
- Targeting microglial TNFα and NF-κB pathways may offer therapeutic strategies for GRN-associated FTD and OCD-like symptoms.
