Cytokines and CNS Development

Abstract

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.

Maternal hospitalization with infection during pregnancy and risk of autism spectrum disorders

“…Multiple animal models of prenatal infection have found evidence of diverse neurobehavioral abnormalities, whether through direct exposure of pregnant mice or rodents to influenza virus, or through non-infectious activation of the maternal immune system (e.g., using RNA poly(I:C) to stimulate an antiviral inflammatory response or lipopolysaccharide to stimulate a bacterial inflammatory response) (Brown and Derkits, 2010;Deverman and Patterson, 2009;Meyer et al, 2011;Miller et al, 2013;Patterson, 2011). The different pattern of associations observed for ASD with and without comorbid intellectual disability reinforces the possibility that higher-functioning and lower-functioning ASD may have different etiologies (Szatmari et al, 2007).…”

“…Cytokines are signaling molecules originally known for their role in the modulation of the immune system. However, cytokines also influence neuronal migration, axonal projections, synapse formation, and neuronal survival during development (Deverman and Patterson, 2009). Dysregulated levels of cytokines during development (e.g., due to maternal infections) therefore may adversely affect neurobehavioral function.…”

Joint Effects of Exposure to Prenatal Infection and Peripubertal Psychological Trauma in Schizophrenia

“…39 Such actions could be mediated via various pathological factors, including increased cytokine secretion, hormonal imbalances, and microand/or macro-nutritional deficiencies, all of which are critical for normal brain development. 12,40,41 Disturbances to early neurodevelopmental programs may increase the vulnerability of the offspring to changes in brain maturational processes in response to peripubertal trauma, and these changes may be sex specific as has been suggested. 17,26 Interference with maturational processes may involve abnormal synaptic pruning, which is one of the main events marking the transition of brain maturation from childhood to adolescence.…”

The Role of the Immune System in Autism Spectrum Disorder

“…There is strong evidence that disruption of normal cytokine levels has a significant role as a risk factor for several neurodevelopmental defects, including schizophrenia and autism (Boulanger and Shatz, 2004;Brown et al, 2004b;Deverman and Patterson, 2009;Hsiao et al, 2013;Ponzio et al, 2007). Smith et al (2007) showed in 2007 that a single injection of the pro-inflammatory cytokine IL-6 to pregnant mice at embryonic day 12.5 lead to offspring deficits in prepulse inhibition (PPI) and latent inhibition (LI), both autism-relevant behaviors; these results were not seen following injection of the pro-inflammatory cytokines IL-1α, TNF-α, or IFN-γ.…”