Perinatal IL-1β-induced inflammation suppresses Tbr2+ intermediate progenitor cell proliferation in the developing hippocampus accompanied by long-term behavioral deficits

Stephanie Veerasammy; Juliette Van Steenwinckel; Tifenn Le Charpentier; Joon Ho Seo; Bobbi Fleiss; Pierre Gressens; Steven W Levison

doi:10.1016/j.bbih.2020.100106

Perinatal IL-1β-induced inflammation suppresses Tbr2⁺ intermediate progenitor cell proliferation in the developing hippocampus accompanied by long-term behavioral deficits

Brain Behav Immun Health. 2020 Jul 17:7:100106. doi: 10.1016/j.bbih.2020.100106. eCollection 2020 Aug.

Authors

Stephanie Veerasammy¹, Juliette Van Steenwinckel^{2

3}, Tifenn Le Charpentier^{2

3}, Joon Ho Seo¹, Bobbi Fleiss^{2

3

4}, Pierre Gressens^{2

3

5}, Steven W Levison¹

Affiliations

¹ Department of Pharmacology, Physiology, and Neuroscience, Rutgers University, New Jersey Medical School, Cancer Center, 205 South Orange Avenue, Newark, NJ, 07103, USA.
² Université de Paris, NeuroDiderot, Inserm, F-75019, Paris, France.
³ PremUP, F-75006, Paris, France.
⁴ School of Health and Biomedical Sciences, RMIT University, Bundoora, 3083, VIC, Australia.
⁵ Centre for the Developing Brain, Division of Imaging Sciences and Biomedical Engineering, King's College London, King's Health Partners, St. Thomas' Hospital, London, SE1 7EH, UK.

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.

Keywords: Anxiety; Autism; Brain development; Maternal immune activation; Memory; Neurogenesis; Systemic inflammation.