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Isolation of Cortical Microglia with Preserved Immunophenotype and Functionality From Murine Neonates
Published on: January 30, 2014
Neonatal peripheral immune challenge activates microglia and inhibits neurogenesis in the developing murine
Peter L P Smith1, Henrik Hagberg, Andrew S Naylor
1Institute of Neuroscience and Physiology, Sahlgrenska Academy, Gothenburg, Sweden.
Insights
Neonatal exposure to lipopolysaccharide (LPS) transiently increases microglia but persistently alters hippocampal inflammation. This early inflammation inhibits neuronal differentiation in the developing hippocampus, potentially impacting later-life health.
Area of Science:
- Neuroscience
- Developmental Biology
- Immunology
Background:
- The early postnatal period is critical for hippocampal development, featuring high rates of neurogenesis and microgliogenesis.
- Inflammation during this sensitive window may disrupt development and increase susceptibility to later-life neurological disorders.
Purpose of the Study:
- To investigate the effects of systemic lipopolysaccharide (LPS) administration on microgliogenesis, inflammation, and neurogenesis in the developing rodent hippocampus.
- To determine if early-life inflammation influences the proliferation, survival, and differentiation of neural progenitor cells.
Main Methods:
- Systemic administration of LPS (1 mg/kg i.p.) to rodents at postnatal day 5.
- Assessment of microgliogenesis using ionized calcium-binding adaptor molecule 1 (Iba1) immunoreactivity.
- Quantitative real-time PCR (qRT-PCR) to analyze hippocampal gene expression related to microglial phenotypes (M1/M2).
- Evaluation of neural progenitor cell regulation and neuronal differentiation in the hippocampal subgranular zone.
Main Results:
- LPS administration caused a transient increase in microglia proliferation, not peripheral macrophage infiltration.
- Persistent dysregulation of M1 and M2 microglial phenotype genes indicated prolonged inflammatory alteration.
- A transient inhibition of neuronal differentiation in type 3 neural progenitor cells was observed up to 2 weeks post-LPS, independent of proliferation or survival changes.
Conclusions:
- Systemic inflammation in early neonatal life is sufficient to alter the hippocampal inflammatory status.
- Early-life inflammation dysregulates the neurogenesis process within the developing hippocampal germinal niche.
- These findings highlight the vulnerability of the developing brain to inflammatory insults and their potential long-term consequences.
Abstract:
The early postnatal period represents an important window in rodent hippocampal development with peak hilar neurogenesis and widespread microgliogenesis occurring in the first week of life. Inflammation occurring during this period may negatively influence development, potentially facilitating or increasing susceptibility to later-life pathology. We administered the Gram-negative bacterial coat protein lipopolysaccharide (LPS) systemically at postnatal day 5 (1 mg/kg i.p.) and assessed potential effects on microgliogenesis, inflammation and neurogenesis in the developing hippocampus. LPS administration led to an acute but transient increase in absolute number and density of ionized calcium-binding adaptor molecule 1-immunoreactive microglia, a change attributable to increased proliferation of central nervous system-resident microglia/microglial precursor cells but not infiltration of peripheral monocyte-derived macrophages. qRT-PCR analysis of hippocampal gene expression showed these LPS-mediated changes to be associated with persistent dysregulation of genes associated with both M1 and M2 microglial phenotypes, indicating prolonged alteration in hippocampal inflammatory status. Further, analysis of progenitor cell regulation in the hippocampal subgranular zone revealed a transient inhibition of the neuronal differentiation pathway up to 2 weeks after LPS administration, a change occurring specifically through effects on type 3 neural progenitor cells and independently of altered cell proliferation or survival of newly born cells. Together, our results show that systemic inflammation occurring during the early neonatal period is sufficient to alter inflammatory status and dysregulate the ongoing process of neurogenesis in the developing hippocampal germinal niche.
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