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Modeling Encephalopathy of Prematurity Using Prenatal Hypoxia-ischemia with Intra-amniotic Lipopolysaccharide in Rats
Published on: November 20, 2015
A unique cerebellar pattern of microglia activation in a mouse model of encephalopathy of prematurity
Luisa Klein1, Juliette Van Steenwinckel2, Bobbi Fleiss2,3
1Department of Neonatology, Charité University Medicine Berlin, Berlin, Germany.
Insights
Perinatal inflammation from interleukin-1 beta (IL-1β) causes cerebellar damage in preterm infants. This inflammation leads to oligodendrocyte pathology and specific cerebellar volume deficits, highlighting a potential therapeutic target.
Area of Science:
- Neuroscience
- Developmental Biology
- Immunology
Background:
- Preterm infants frequently exhibit cerebellar pathologies linked to long-term neurodevelopmental deficits.
- Inflammation during the preterm period is a significant risk factor for brain injury.
- Understanding the mechanisms of cerebellar damage in prematurity is crucial for developing interventions.
Purpose of the Study:
- To investigate the causes of cerebellar damage in a mouse model of inflammation-induced encephalopathy of prematurity.
- To identify the specific cellular and molecular changes in the cerebellum following systemic pro-inflammatory cytokine administration.
Main Methods:
- Systemic administration of pro-inflammatory interleukin-1 beta (IL-1β) to mice between postnatal days 1-5.
- Structural magnetic resonance imaging (MRI) to assess cerebellar volumes.
- Immunohistochemistry to analyze oligodendrocyte and microglial populations (OLIG2+, IBA1+).
- Western blotting to quantify myelin proteins (MBP, MAG).
- Transcriptomic analysis of isolated cerebellar and cerebral microglia.
Main Results:
- Systemic IL-1β treatment caused significant reductions in cerebellar lobules I and II gray and white matter volumes starting from postnatal day 15.
- Oligodendrocyte damage, evidenced by reduced OLIG2+ cell proliferation and decreased myelin proteins (MBP, MAG), preceded MRI-detectable volume changes.
- Increased density and proliferation of cerebellar microglia (IBA1+) were observed.
- Cerebellar microglia exhibited unique type I interferon signaling dysregulation compared to cerebral microglia.
Conclusions:
- Perinatal inflammation induced by IL-1β leads to specific cerebellar volume deficits in a mouse model.
- These deficits are likely caused by oligodendrocyte pathology secondary to microglial activation.
- Targeting sustained type I interferon signaling in cerebellar microglia may represent a novel therapeutic strategy for preventing preterm brain injury.
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.
