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Published on: November 20, 2015
Perinatal IL-1β-induced inflammation suppresses Tbr2+ intermediate progenitor cell proliferation in the developing
Stephanie Veerasammy1, Juliette Van Steenwinckel2,3, Tifenn Le Charpentier2,3
1Department of Pharmacology, Physiology, and Neuroscience, Rutgers University, New Jersey Medical School, Cancer Center, 205 South Orange Avenue, Newark, NJ, 07103, USA.
Insights
Perinatal inflammation, triggered by interleukin-1 beta (IL-1β), impairs hippocampal development in mice, leading to lasting anxiety and spatial memory deficits. This research sheds light on cognitive impairments in premature infants.
Area of Science:
- Neuroscience
- Developmental Biology
- Immunology
Background:
- Maternal infections during pregnancy are linked to premature birth and developmental deficits in children.
- Pregnancy-induced inflammation in rodents mirrors human studies, causing offspring cognitive and behavioral issues.
- Inflammation reduces neurogenesis in the hippocampus, a key area for memory and cognition.
Purpose of the Study:
- To investigate how interleukin-1 beta (IL-1β)-mediated neuroinflammation affects hippocampal development and leads to cognitive/behavioral abnormalities.
- To determine if IL-1β exposure during early life impacts hippocampal growth and function.
Main Methods:
- Neonatal Swiss Webster mice received twice-daily injections of IL-1β (10 ng/g) for the first 5 days of life.
- Neurogenesis and progenitor cell proliferation in the dentate gyrus (DG) were assessed.
- In vitro studies examined IL-1α and IL-1β effects on cell cycle progression.
- Mice were behaviorally tested for anxiety, exploratory behavior, working memory, and spatial memory.
Main Results:
- IL-1β administration increased hippocampal IL-1α levels and acutely reduced neural progenitor proliferation in the DG.
- In vitro, IL-1α and IL-1β induced G1/S cell cycle arrest, decreasing progenitor proliferation but increasing neural stem cell frequency.
- Treated mice exhibited anxiety behaviors in adolescence and adulthood.
- Adult mice showed deficits in long-term spatial memory but not working memory.
Conclusions:
- Perinatal inflammation negatively impacts the developing hippocampus, causing persistent behavioral deficits.
- IL-1β exposure during early life alters hippocampal development and function, contributing to cognitive impairments.
- These findings offer insights into the origins of cognitive and behavioral issues in prematurely born infants.
Abstract:
Meta-analyses have revealed associations between the incidence of maternal infections during pregnancy, premature birth, smaller brain volumes, and subsequent cognitive, motor and behavioral deficits as these children mature. Inflammation during pregnancy in rodents produces cognitive and behavioral deficits in the offspring that are similar to those reported in human studies. These deficits are accompanied by decreased neurogenesis and proliferation in the subgranular zone (SGZ) of the dentate gyrus (DG) of the hippocampus. As systemically administering interleukin-1 β (IL-1β) to neonatal mice recapitulates many of the brain abnormalities seen in premature babies including developmental delays, the goal of this study was to determine whether IL-1-mediated neuroinflammation would affect hippocampal growth during development to produce cognitive and behavioral abnormalities. For these studies, 10 ng/g IL-1β was administered twice daily to Swiss Webster mice during the first 5 days of life, which increased hippocampal levels of IL-1α and acutely reduced the proliferation of Tbr2+ neural progenitors in the DG. In vitro, both IL-1α and IL-1β produced G1/S cell cycle arrest that resulted in reduced progenitor cell proliferation within the transit amplifying progenitor cell cohort. By contrast, IL-1β treatment increased neural stem cell frequency. Upon terminating IL-1β treatment, the progenitor cell pool regained its proliferative capacity. An earlier study that used this in vivo model of perinatal inflammation showed that mice that received IL-1β as neonates displayed memory deficits which suggested abnormal hippocampal function. To evaluate whether other cognitive and behavioral traits associated with hippocampal function would also be altered, mice were tested in tasks designed to assess exploratory and anxiety behavior as well as working and spatial memory. Interestingly, mice that received IL-1β as neonates showed signs of anxiety in several behavioral assays during adolescence that were also evident in adulthood. Additionally, these mice did not display working memory deficits in adulthood, but they did display deficits in long-term spatial memory. Altogether, these data support the view that perinatal inflammation negatively affects the developing hippocampus by producing behavioral deficits that persist into adulthood. These data provide a new perspective into the origin of the cognitive and behavioral impairments observed in prematurely-born sick infants.
