Neonatal Peripheral Immune Challenge Activates Microglia and Inhibits Neurogenesis in the Developing Murine Hippocampus

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.

The Developing Microbiome of the Preterm Infant

“…25,26 Thus altered microbial communities could influence neurodevelopmental outcomes. Neurodevelopmental outcomes are of prime importance to neonatology.…”

A Critical Review of Models of Perinatal Infection

“…Similarly, a higher dose of LPS (10 mg/kg s.c.) in P2 mice was associated with impaired oligodendrocyte maturation and reduced myelin production, without oligodendrocyte cell death or axonal injury, while a similar insult at P3, P4 or P5 had no obvious effects [88]. Nevertheless, a single dose of 1 mg/kg LPS in P5 rat pups was associated with persistent changes in microglial-phenotype-related genes, with a transient inhibition of the neuronal differentiation pathway for up to 2 weeks [89]. Consistent with persistent changes in response to inflammation, although neonatal LPS exposure at P5 did not lead to death of dopaminergic neurons in the substantia nigra, there were persistent functional alterations in the dopaminergic system and the substantia nigra at P70, as well as increased susceptibility to damage by very low-dose rotenone that was nontoxic in control animals [90].…”

Inflammation early in life is a vulnerability factor for emotional behavior at adolescence and for lipopolysaccharide-induced spatial memory and neurogenesis alteration at adulthood

“…In neonate rodents, immune challenge has been reported to stimulate the production of proinflammatory cytokines, such as interleukin(IL)-1β, IL-6 and tumor necrosis alpha (TNFα), both at the periphery and in the brain [7], together with enhanced corticosterone levels [8]. These factors have been proposed to adversely impacts fetal brain development [9,10] such as hippocampal neurogenesis [11]. Studies in rodents have shown that postnatal day (PND)14 is a crucial period for brain network maturation.…”