Specific neurodevelopmental damage in mice offspring following maternal inflammation during pregnancy
Introduction
Intrauterine inflammation is a major risk for pre-term delivery and offspring neurodevelopmental brain damage, which may result in neurological disorders and mental disability (Dammann et al., 2002, Saliba and Henrot, 2001). Maternal intrauterine infection is thought to affect the immature brain by the induction of pro-inflammatory cytokines. The presence of cytokines in the three relevant maternal/fetal compartments (uterus, fetal circulation, and fetal brain) and the ability of the cytokines to cross boundaries (placenta and blood–brain barrier) between these compartments has been confirmed (Fidel et al., 1994).
The pro-inflammatory cytokines, tumor necrosis factor-α (TNFα), interleukin-1 (IL-1) and IL-6 have been associated with intrauterine infection, pre-term delivery, neonatal infections and neonatal brain damage. IL-1, IL-6, and TNFα share several biological functions, even though they are structurally different and bind to different receptors (Dinarello, 2000). In the brain, these cytokines are expressed in both glia cells and neurons. In addition to their function in the immune response, these cytokines modulate neuron development and function. TNFα is involved in the regulation of neurite growth (Neumann et al., 2002), affect neuronal survival (Yang et al., 2002, Barker et al., 2001) and regulate AMPA receptors expression (Beattie et al., 2002). Recently, the involvement of TNFα in the regulation of hippocampal development and function was demonstrated (Golan et al., 2004, Aloe et al., 1999). IL-1b is involved in the regulation of synaptic plasticity; the expression of the IL-1beta gene was specifically increased during long-term potentiation (LTP), and the blocking of LTP by NMDA receptor antagonist prevented the increase in IL-1 beta gene expression (Schneider et al., 1998). The administration of lipopolysaccharide (LPS) to pregnant rats increased the expression of TNFα and IL-1b mRNA in a fetal brain in a dose-dependent manner and modified the glia cell populations a week after the application (Cai et al., 2000).
At gestation day 17 in the mouse fetus most of the brain regions are already created. At this age in the cerebral cortex and hippocampus the neurons are already formed, however, neuronal migration, maturation and synaptogenesis still undergo (Bayer, 1980a, Bayer, 1980b, Altman and Bayer, 1990).
Based on the above data, we hypothesized that maternal inflammation at gestation day 17, will perturb offspring accurate neurogenesis and will be reflected by offspring behavioral impairment. We suggest the neurotrophic factors as possible mediators of the inflammation process.
Our results demonstrate that maternal administration of LPS altered the learning and memory performance in the adult offspring. This effect was associated with specific histopathological damage in the hippocampus region and with the increased expression of NGF and BDNF in the thalamus of the adult offspring.
Section snippets
Study design
Pregnant Jackson Black C-57 mice were used. All pregnant mice were treated at gestation day 17. The mice were randomly assigned to one of two groups: (1) saline injections (intraperitoneal; i.p.) – control group, fetus and newborn examinations; (2) E. coli LPS (Sigma Inc, St. Louis, MO, USA) injections (0.12 μg/g mouse/100 μl, i.p.) – study group, fetus and newborn examinations.
The mouse colony was maintained in a 12:12-h light/dark schedule; food and water were provided ad libitum. All animal
Inflammatory response in fetal brains following maternal inflammation
Induction of cytokines in fetus following maternal administration with LPS was previously demonstrated (Cai et al., 2000). In the present study we examined the pro-inflammatory cytokine, IL-6 (as a representative of pro-inflammatory cytokines), to confirm the inflammatory effect of LPS in our system. We administrated a single dose of LPS that induced cytokine production in the fetal brain without inducing pre-term delivery. When a dose of 0.3 μg/kg of LPS was injected into pregnant mice at
Discussion
The short, systemic maternal inflammation by the i.p. administration of LPS at E17 produced particular long-term effects in the adult offspring, as detected by specific alterations in hippocampus histology and the impairment of distinct aspects of learning and memory. These findings may result from a variation in the sensitivity of different regions in the fetal brain to products of the inflammatory response. Among the proteins produced by the inflammatory response are the pro-inflammatory
Acknowledgments
We thank Prof. Ora Kofman from the Behavioral Sciences Department in Ben-Gurion University for her help with the passive avoidance and hot plate tests.
This study was supported by the Goldman foundation in the Faculty of Health Sciences, Ben-Gurion University of the Negev, Israel to Dr. Golan and partially supported by BSF grant to Dr. Huleihel and Dr. Hallak.
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