Cytokines and CNS Development

Division of Biology, California Institute of Technology, 1200 East California Boulevard M/C 216-76, Pasadena, CA 91125, USA.
Neuron (Impact Factor: 15.05). 10/2009; 64(1):61-78. DOI: 10.1016/j.neuron.2009.09.002
Source: PubMed


Cytokines are pleotrophic proteins that coordinate the host response to infection as well as mediate normal, ongoing signaling between cells of nonimmune tissues, including the nervous system. As a consequence of this dual role, cytokines induced in response to maternal infection or prenatal hypoxia can profoundly impact fetal neurodevelopment. The neurodevelopmental roles of individual cytokine signaling pathways are being elucidated through gain- and loss-of-function studies in cell culture and model organisms. We review this work with a particular emphasis on studies where cytokines, their receptors, or components of their signaling pathways have been altered in vivo. The extensive and diverse requirements for properly regulated cytokine signaling during normal nervous system development revealed by these studies sets the foundation for ongoing and future work aimed at understanding how cytokines induced normally and pathologically during critical stages of fetal development alter nervous system function and behavior later in life.

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Available from: Paul H Patterson
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    • "Figures of the 3-day C. albicans-/fluconazole-treated group are not depicted here. Images taken at ×100 magnification (insert at ×400 magnification), scale bar = 500 μm addition, IL-6 was shown to be involved in the inhibition of neurogenesis [28] and the development of hyperexcitable neurological conditions including epilepsy, psychoses, anxiety, and autism spectrum disorders in experimental models [34]. Notably, increased circulatory IL-6 concentrations were not always paralleled by positive blood cultures in our study. "
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    ABSTRACT: Intra-amniotic Candida albicans (C. Albicans) infection is associated with preterm birth and high morbidity and mortality rates. Survivors are prone to adverse neurodevelopmental outcomes. The mechanisms leading to these adverse neonatal brain outcomes remain largely unknown. To better understand the mechanisms underlying C. albicans-induced fetal brain injury, we studied immunological responses and structural changes of the fetal brain in a well-established translational ovine model of intra-amniotic C. albicans infection. In addition, we tested whether these potential adverse outcomes of the fetal brain were improved in utero by antifungal treatment with fluconazole. Pregnant ewes received an intra-amniotic injection of 10 7 colony-forming units C. albicans or saline (controls) at 3 or 5 days before preterm delivery at 0.8 of gestation (term ~ 150 days). Fetal intra-amniotic/intra-peritoneal injections of fluconazole or saline (controls) were administered 2 days after C. albicans exposure. Post mortem analyses for fungal burden, peripheral immune activation, neuroinflammation, and white matter/neuronal injury were performed to determine the effects of intra-amniotic C. albicans and fluconazole treatment. Intra-amniotic exposure to C. albicans caused a severe systemic inflammatory response, illustrated by a robust increase of plasma interleukin-6 concentrations. Cerebrospinal fluid cultures were positive for C. albicans in the majority of the 3-day C. albicans-exposed animals whereas no positive cultures were present in the 5-day C. albicans-exposed and fluconazole-treated animals. Although C. albicans was not detected in the brain parenchyma, a neuroinflammatory response in the hippocampus and white matter was seen which was characterized by increased microglial and astrocyte activation. These neuroinflammatory changes were accompanied by structural white matter injury. Intra-amniotic fluconazole reduced fetal mortality but did not attenuate neuroinflammation and white matter injury. Intra-amniotic C. albicans exposure provoked acute systemic and neuroinflammatory responses with concomitant white matter injury. Fluconazole treatment prevented systemic inflammation without attenuating cerebral inflammation and injury.
    Full-text · Article · Feb 2016 · Journal of Neuroinflammation
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    • "Thus, increases in maternal interleukin-6 (IL-6) alter many parameters that influence fetal growth, such as nutrient transfer, anoxia, and vascular permeability (Desai et al., 2002; Kendall and Peebles, 2005). Furthermore, IL-6 can act directly on progenitor cells to regulate fetal neurogenesis and gliogenesis (Deverman and Patterson, 2009). IL-1, IL-2, and IL-6 also influence the release of monoamines in the hippocampus and other brain regions (Libbey et al., 2005). "
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    ABSTRACT: Autism spectrum disorders (ASD) are among the most severe developmental psychiatric disorders known today, characterized by impairments in communication and social interaction and stereotyped behaviors. However, no specific treatments for ASD are as yet available. By enabling selective genetic, neural, and pharmacological manipulations, animal studies are essential in ASD research. They make it possible to dissect the role of genetic and environmental factors in the pathogenesis of the disease, circumventing the many confounding variables present in human studies. Furthermore, they make it possible to unravel the relationships between altered brain function in ASD and behavior, and are essential to test new pharmacological options and their side-effects. Here, we first discuss the concepts of construct, face, and predictive validity in rodent models of ASD. Then, we discuss how ASD-relevant behavioral phenotypes can be mimicked in rodents. Finally, we provide examples of environmental and genetic rodent models widely used and validated in ASD research. We conclude that, although no animal model can capture, at once, all the molecular, cellular, and behavioral features of ASD, a useful approach is to focus on specific autism-relevant behavioral features to study their neural underpinnings. This approach has greatly contributed to our understanding of this disease, and is useful in identifying new therapeutic targets.
    Full-text · Article · Sep 2015 · Behavioural pharmacology
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    • "This complicates elucidating the site where the cytokines act upon to potentially alter brain development since they can act directly on neural progenitors and neurons ( Bauer et al . , 2007 ; Deverman and Patterson , 2009 ) . For example , IL - 6 and LIF can influence the differentiation of neural progenitor cells ( Nakanishi et al . "
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    ABSTRACT: Several studies have indicated that inflammation during pregnancy increases the risk for the development of neuropsychiatric disorders in the offspring. Morphological brain abnormalities combined with deviations in the inflammatory status of the brain can be observed in patients of both autism and schizophrenia. It was shown that acute infection can induce changes in maternal cytokine levels which in turn are suggested to affect fetal brain development and increase the risk on the development of neuropsychiatric disorders in the offspring. Animal models of maternal immune activation reproduce the etiology of neurodevelopmental disorders such as schizophrenia and autism. In this study the poly (I:C) model was used to mimic viral immune activation in pregnant mice in order to assess the activation status of fetal microglia in these developmental disorders. Because microglia are the resident immune cells of the brain they were expected to be activated due to the inflammatory stimulus. Microglial cell density and activation level in the fetal cortex and hippocampus were determined. Despite the presence of a systemic inflammation in the pregnant mice, there was no significant difference in fetal microglial cell density or immunohistochemically determined activation level between the control and inflammation group. These data indicate that activation of the fetal microglial cells is not likely to be responsible for the inflammation induced deficits in the offspring in this model.
    Full-text · Article · Aug 2015 · Frontiers in Cellular Neuroscience
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