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Review
, 7, 180

Cytokines and the Neurodevelopmental Basis of Mental Illness

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Review

Cytokines and the Neurodevelopmental Basis of Mental Illness

Udani Ratnayake et al. Front Neurosci.

Abstract

Epidemiological studies suggest that prenatal exposure to different types of viral or bacterial infections may be associated with similar outcomes; i.e., an increased risk of mental illness disorders in the offspring. Infections arising from various causes have similar debilitating effects in later life, suggesting that the exact pathogen may not be the critical factor in determining the neurological and cognitive outcome in the offspring. Instead, it is thought that response of the innate immune system, specifically the increased production of inflammatory cytokines, may be the critical mediator in altering fetal brain development pre-disposing the offspring to mental illness disorders later in life. Inflammatory cytokines are essential for normal brain development. Factors such as the site of cytokine production, a change in balance between anti- and pro- inflammatory cytokines, placental transfer of cytokines, the effects of cytokines on glial cells, and the effects of glucocorticoids are important when evaluating the impact of maternal infection on fetal brain development. Although it is clear that cytokines are altered in the fetal brain following maternal infection, further evidence is required to determine if cytokines are the critical factor that alters the trajectory of brain development, subsequently leading to postnatal behavioral and neurological abnormalities.

Keywords: cytokines; glial cells; infection; mental illness; pregnancy; stress.

Figures

Figure 1
Figure 1
The relationship between cytokines and hypothalamic-pituitary-adrenal (HPA) axis. Cytokines, produced in response to an infection, can stimulate the release of corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) from the hypothalamus. These hormones stimulate the secretion of adrenocorticotrophic hormone (ACTH) from the anterior pituitary gland, and, in turn, the secretion of glucocorticoids (GC) from the adrenal cortex. During fetal life, excess GC can change the long-term function of the HPA-axis and if exposed to the fetal brain, GC can also modify brain development. In addition, GC can inhibit the induction of pro-inflammatory cytokines while stimulating the production of anti-inflammatory cytokines, a process that can also act to change the function of HPA-axis.
Figure 2
Figure 2
Number of Iba1 immunopositive cell bodies (A) and percentage Iba1 staining in the hippocampus in PBS (solid bars) and Poly I:C (dashed bars) prenatally exposed animals at 1d (white bars) and 100d (gray bars) postnatal age. Iba1 immunopositive staining in the hippocampus from animals prenatally exposed to PBS (C) and Poly I: (D) at 1d postnatal age. Note an increased number Iba1 immunopositive cell bodies in the Poly I:C (A,D) neonatal brains compared to the PBS (C). Although, note an increase in the percentage of Iba1 staining in PBS neonatal brains (B,C) compared to Poly I:C (D). The combination of these two findings, of more microglial cell bodies and fewer branching processes, make it possible to conclude that there are more activated, and fewer ramified, microglia in the neonatal hippocampus of animals born to mothers administered with the viral mimetic, Poly I:C. The data are shown as means ± SEM in all graphs. * refers p < 0.05. Scale bar = 100μM in (C,D). Adapted from Ratnayake et al. (2012).

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