Enhanced susceptibility to seizures modulated by high interleukin‐1β levels during early life malnutrition

Simão, Fabrício; Oliveira, Victória Habekost; Nunes, Magda L.

doi:10.1002/dneu.22381

Cited by 7 publications

(5 citation statements)

References 65 publications

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“…One reason that the hippocampus is especially sensitive to high levels of IL-1 is that the IL-1R1 is expressed at extraordinarily high levels within the DG of the hippocampus ( Cunningham et al., 1992 ). The regulated expression of both IL-1R1 ( Simao et al., 2016 ) and IL-1β during early postnatal development of the hippocampus ( Garay et al., 2013 ) suggests that this cytokine may have an important role during hippocampal development.…”

Section: Introductionmentioning

confidence: 99%

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

Veerasammy

Steenwinckel

Charpentier

et al. 2020

Brain, Behavior, & Immunity - Health

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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.

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Section: Introductionmentioning

confidence: 99%

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

Veerasammy

Steenwinckel

Charpentier

et al. 2020

Brain, Behavior, & Immunity - Health

View full text Add to dashboard Cite

show abstract

Section: Introductionmentioning

confidence: 99%

“…One reason that the hippocampus is especially sensitive to high levels of IL-1 is that the IL-1 receptor is expressed at extraordinarily high levels within the DG of the hippocampus (Cunningham et al, 1992). The regulated expression of both IL-1R1 (Simao et al, 2016) and IL-1β during early postnatal development of the hippocampus (Garay et al, 2013) suggests that this cytokine may have an important role during hippocampal development.In vitro studies have shown that IL-1β can negatively affect hippocampal neurogenesis. Koo and Duman 2008 performed in vitro studies of adult rat hippocampal NPs and showed that NPs express IL-1R1 and that activation of IL-1R1 by IL-1β decreased NP proliferation via NF-κB signaling (Koo and Duman, 2008).Similarly, in vitro studies on embryonic rat hippocampal NPs by Green and colleagues revealed decreased NP proliferation and decreased neuronal differentiation as a result of IL-1β signaling through IL-1R1 (Green et al, 2012), supporting the conclusion that IL-1R1 signaling negatively affects hippocampal NPs.…”

mentioning

confidence: 99%

Perinatal IL-1β-induced Inflammation Suppresses Tbr2+ Intermediate Progenitor Cell Proliferation in the Developing Hippocampus accompanied by Long-Term Behavioral Deficits

Veerasammy

Steenwinckel

Lecharpentier

et al. 2020

Preprint

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Running Title: Perinatal Inflammation Perturbs Hippocampal Neurogenesis Highlights:• Systemic inflammation during the first 5 days of life increases hippocampal pro-inflammatory cytokines and chemokines• Neuroinflammation reduces Tbr2 + neural progenitor cell proliferation in the dentate gyrus.• IL-1 arrests the cell cycle of Tbr-2 + progenitors and enriches for neural stem cells.• Adolescent mice that experienced neonatal systemic inflammation have a persistent anxiety disorder.• Mice that experienced neonatal systemic inflammation have deficits in spatial memory as adults. 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 producing behavioral deficits that persist into adulthood. These data provide a new perspective into the origin of the cognitive and behavioral impairments observed in prema...

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“…MIA and other forms of maternal stress, such as separation of dam from pups or early handling of pups, may also be considered as an early life stressor which aggravates epileptogenesis in both status epilepticus (SE) and kindling models (Salzberg et al, 2007). Additionally, stress resulting from transport of dams during pregnancy, as well as maternal behaviors and early postnatal malnutrition, have all been demonstrated to promote susceptibility to KA or amygdala kindling-induced seizures of the offspring during later life (Salzberg et al, 2007;Moriyama et al, 2013;Simao et al, 2016).…”

Section: Maternal and Environmental Stress Throughout Developmentmentioning

confidence: 99%

Immune Challenges and Seizures: How Do Early Life Insults Influence Epileptogenesis?

2020

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The development of epilepsy, a process known as epileptogenesis, often occurs later in life following a prenatal or early postnatal insult such as cerebral ischemia, stroke, brain trauma, or infection. These insults share common pathophysiological pathways involving innate immune activation including neuroinflammation, which is proposed to play a critical role in epileptogenesis. This review provides a comprehensive overview of the latest preclinical evidence demonstrating that early life immune challenges influence neuronal hyperexcitability and predispose an individual to later life epilepsy. Here, we consider the range of brain insults that may promote the onset of chronic recurrent spontaneous seizures at adulthood, spanning intrauterine insults (e.g. maternal immune activation), perinatal injuries (e.g. hypoxic-ischemic injury, perinatal stroke), and insults sustained during early postnatal life-such as fever-induced febrile seizures, traumatic brain injuries, infections, and environmental stressors. Importantly, all of these insults represent, to some extent, an immune challenge, triggering innate immune activation and implicating both central and systemic inflammation as drivers of epileptogenesis. Increasing evidence suggests that pro-inflammatory cytokines such as interleukin-1 and subsequent signaling pathways are important mediators of seizure onset and recurrence, as well as neuronal network plasticity changes in this context. Our current understanding of how early life immune challenges prime microglia and astrocytes will be explored, as well as how developmental age is a critical determinant of seizure susceptibility. Finally, we will consider the paradoxical phenomenon of preconditioning, whereby these same insults may conversely provide neuroprotection. Together, an improved appreciation of the neuroinflammatory mechanisms underlying the long-term epilepsy risk following early life insults may provide insight into opportunities to develop novel immunological antiepileptogenic therapeutic strategies.

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Enhanced susceptibility to seizures modulated by high interleukin‐1β levels during early life malnutrition

Cited by 7 publications

References 65 publications

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

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

Perinatal IL-1β-induced Inflammation Suppresses Tbr2+ Intermediate Progenitor Cell Proliferation in the Developing Hippocampus accompanied by Long-Term Behavioral Deficits

Immune Challenges and Seizures: How Do Early Life Insults Influence Epileptogenesis?

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