title: Abnormal microglial activation in the Cstb(-/-) mouse, a model for progressive myoclonus epilepsy, EPM1.
abstract: Progressive myoclonus epilepsy of Unverricht-Lundborg type (EPM1) is an autosomal-recessively inherited neurodegenerative disorder characterized by severely incapacitating myoclonus, seizures, and ataxia, and caused by loss-of-function mutations in the cystatin B gene (CSTB). A central neuropathological finding in the Cstb(-/-) mouse, an animal model for EPM1, is early microglial activation, which precedes astroglial activation, neuronal loss, and onset of myoclonus, thus implying a critical role for microglia in EPM1 pathogenesis. Here, we characterized phenotypic and functional properties of microglia from Cstb(-/-) mice utilizing brain tissue, microglia directly isolated from the brain, and primary microglial cultures. Our results show significantly higher Cstb mRNA expression in microglia than in neurons and astrocytes. In Cstb(-/-) mouse brain, expression of the inflammatory marker p-p38 MAPK and the proportion of both pro-inflammatory M1 and anti-inflammatory M2 microglia is higher than in control mice. Moreover, M1/M2 polarization of microglia in presymptomatic Cstb(-/-) mice is, compared to control mice, skewed towards M2 type at postnatal day 14 (P14), but towards M1 type at P30, a time point associated with onset of myoclonus. At this age, the high expression of both pro-inflammatory inducible nitric oxide synthase (iNOS) and anti-inflammatory arginase 1 (ARG1) in Cstb(-/-) mouse cortex is accompanied by the presence of peripheral immune cells. Consistently, activated Cstb(-/-) microglia show elevated chemokine release and chemotaxis. However, their MHCII surface expression is suppressed. Taken together, our results link CSTB deficiency to neuroinflammation with early activation and dysfunction of microglia and will open new avenues for therapeutic interventions for EPM1.
authors.affiliation: Folkhälsan Institute of Genetics, Haartmaninkatu 8, 00014, Helsinki, Finland; Haartman Institute, Department of Medical Genetics and Research Program's Unit, Molecular Neurology, University of Helsinki, Haartmaninkatu 8, 00014, Helsinki, Finland; Neuroscience Center, University of Helsinki, Viikinkaari 4, 00014, Helsinki, Finland.
authors.forename: Olesya
authors.initials: O
authors.lastname: Okuneva
authors.forename: Inken
authors.initials: I
authors.lastname: Körber
authors.forename: Zhilin
authors.initials: Z
authors.lastname: Li
authors.forename: Li
authors.initials: L
authors.lastname: Tian
authors.forename: Tarja
authors.initials: T
authors.lastname: Joensuu
authors.forename: Outi
authors.initials: O
authors.lastname: Kopra
authors.forename: Anna-Elina
authors.initials: AE
authors.lastname: Lehesjoki
mesh_terms: D000818:Animals; D001119:Arginase / Q000378:metabolism; D001253:Astrocytes / Q000378:metabolism; D001921:Brain / Q000276:immunology*; D002478:Cells, Cultured; D055313:Cystatin B / Q000172:deficiency* / Q000235:genetics; D004195:Disease Models, Animal; D005802:Genes, MHC Class II / Q000502:physiology; D006098:Granulocytes / Q000502:physiology; D008264:Macrophages / Q000502:physiology; D057507:Mice, 129 Strain; D017628:Microglia / Q000502:physiology*; D015213:Neuroimmunomodulation / Q000502:physiology; D009474:Neurons / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D013601:T-Lymphocytes / Q000502:physiology; D020194:Unverricht-Lundborg Syndrome / Q000276:immunology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C524992:Cstb protein, mouse; D012333:RNA, Messenger; D055313:Cystatin B; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D048051:p38 Mitogen-Activated Protein Kinases; C544448:Arg1 protein, mouse; D001119:Arginase
keywords: M1/M2; chemokine; cystatin B; neuroinflammation; p38 MAPK; pro-inflammatory microglia