A unique cerebellar pattern of microglia activation in a mouse model of encephalopathy of prematurity

Luisa Klein; Juliette Van Steenwinckel; Bobbi Fleiss; Till Scheuer; Christoph Bührer; Valerie Faivre; Sophie Lemoine; Corinne Blugeon; Leslie Schwendimann; Zsolt Csaba; Cindy Bokobza; Dulcie A Vousden; Jason P Lerch; Anthony C Vernon; Pierre Gressens; Thomas Schmitz

doi:10.1002/glia.24190

Original language	English
Pages (from-to)	1699-1719
Number of pages	21
Journal	Glia
Volume	70
Issue number	9
Early online date	17 May 2022
DOIs	https://doi.org/10.1002/glia.24190
E-pub ahead of print	17 May 2022
Published	Sep 2022
Additional links	Link to publication in Scopus

Bibliographical note

Funding Information: Cerebral Palsy Alliance Research Foundation; Deutsche Forschungsgemeinschaft; Fondation pour la Recherche sur le cerveau; Horizon 2020 Framework Programme, Grant/Award Number: 874721/PREMSTEM; Institut National de la Santé et de la Recherche Médicale; Medical Research Council, Grant/Award Number: MR/N025377/1; NeurATRIS Funding information Funding Information: ThS, TiS and LK's research was supported by funding from Deutsche Forschungsgemeinschaft – DFG, SCHM3007/3-2 and SCHE 2078/2-1, and from Förderverein für frühgeborene Kinder an der Charité e.V. ACV acknowledges financial support for this study from the Medical Research Council (New Investigator Research Grant [NIRG], MR/N025377/1). The work (at King's College, London) was also supported by the Medical Research Council (MRC) Centre grant (MR/N026063/1). PG, JVS, BF, LS, and ZC's research was supported by funding from Inserm, Université de Paris, Fondation de France, Fondation pour la Recherche sur le Cerveau, Fondation Grace de Monaco, Horizon 2020 Framework Program of the European Union (grant agreement no. 874721/PREMSTEM), and an additional grant from Investissement d'Avenir -ANR-11-INBS-0011 NeurATRIS. BF's research was also funded by the Cerebral Palsy Alliance, Australia. Funding Information: ThS, TiS and LK's research was supported by funding from Deutsche Forschungsgemeinschaft – DFG, SCHM3007/3‐2 and SCHE 2078/2‐1, and from Förderverein für frühgeborene Kinder an der Charité e.V. ACV acknowledges financial support for this study from the Medical Research Council (New Investigator Research Grant [NIRG], MR/N025377/1). The work (at King's College, London) was also supported by the Medical Research Council (MRC) Centre grant (MR/N026063/1). PG, JVS, BF, LS, and ZC's research was supported by funding from Inserm, Université de Paris, Fondation de France, Fondation pour la Recherche sur le Cerveau, Fondation Grace de Monaco, Horizon 2020 Framework Program of the European Union (grant agreement no. 874721/PREMSTEM), and an additional grant from Investissement d'Avenir ‐ANR‐11‐INBS‐0011 NeurATRIS. BF's research was also funded by the Cerebral Palsy Alliance, Australia. Publisher Copyright: © 2022 The Authors. GLIA published by Wiley Periodicals LLC.

Abstract

Preterm infants often show pathologies of the cerebellum, which are associated with impaired motor performance, lower IQ and poor language skills at school ages. Using a mouse model of inflammation-induced encephalopathy of prematurity driven by systemic administration of pro-inflammatory IL-1β, we sought to uncover causes of cerebellar damage. In this model, IL-1β is administered between postnatal day (P) 1 to day 5, a timing equivalent to the last trimester for brain development in humans. Structural MRI analysis revealed that systemic IL-1β treatment induced specific reductions in gray and white matter volumes of the mouse cerebellar lobules I and II (5% false discovery rate [FDR]) from P15 onwards. Preceding these MRI-detectable cerebellar volume changes, we observed damage to oligodendroglia, with reduced proliferation of OLIG2+ cells at P10 and reduced levels of the myelin proteins myelin basic protein (MBP) and myelin-associated glycoprotein (MAG) at P10 and P15. Increased density of IBA1+ cerebellar microglia were observed both at P5 and P45, with evidence for increased microglial proliferation at P5 and P10. Comparison of the transcriptome of microglia isolated from P5 cerebellums and cerebrums revealed significant enrichment of pro-inflammatory markers in microglia from both regions, but cerebellar microglia displayed a unique type I interferon signaling dysregulation. Collectively, these data suggest that perinatal inflammation driven by systemic IL-1β leads to specific cerebellar volume deficits, which likely reflect oligodendrocyte pathology downstream of microglial activation. Further studies are now required to confirm the potential of protective strategies aimed at preventing sustained type I interferon signaling driven by cerebellar microglia as an important therapeutic target.

King's College London

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