Abnormal microglial activation in the Cstb super(-/-) mouse, a model for progressive myoclonus epilepsy, EPM1

• Published in: Glia Vol. 63; no. 3; pp. 400 - 411
• Main Authors: Okuneva, Olesya, Korber, Inken, Li, Zhilin, Tian, Li, Joensuu, Tarja, Kopra, Outi, Lehesjoki, Anna-Elina
• Format: Journal Article
• Language: English
• Published: 01.03.2015
• ISSN: 0894-1491; 1098-1136
• DOI: 10.1002/glia.22760

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 super(-/-) 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 super(-/-) 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 super(-/-) 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 super(-/-) 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 super(-/-) mouse cortex is accompanied by the presence of peripheral immune cells. Consistently, activated Cstb super(-/-) 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. GLIA 2015; 63:400-411 Main points * Microglia in Cstb super(-/-) mice, a model for progressive myoclonus epilepsy, are dysfunctional. * They show skewed M1/M2 polarization, increased chemokine release and chemotaxis. * Reduced MHCII surface expression implies compromised antigen presentation.