Cytokines and neuroinflammation have received increasing attention in regards to brain pathologies in mental health disorders, including Autism Spectrum Disorder (ASD). While cytokines feature importantly in the regulation of inflammatory and other immune responses, they are also involved in aspects of normal brain development, rendering the formation of functional neural network, in areas such as cerebral cortex, vulnerable to disrupted cytokine production. Abnormal serotonin (5-HT) neurotransmission is similarly implicated in the etiology of many mental health disorders. In ASD, in particular, structural and functional brain pathologies are consistent with effects of developmental serotonin imbalances, as characterized in animal models. Moreover, genetic and blood borne markers provide evidence for systemic serotonin imbalances in a significant subpopulation of individuals with ASD. We previously developed a mouse model to study the effects of neonatal, focal cortical 5-HT depletion at birth, for structural and functional similarities to ASD phenotypes. We have found that compared to controls, neonatally 5-HT deficient Balb/CByJ mice display, as adults, deficits in social behavior, novelty aversion and other ASD relevant behaviors. Serotonin depletion also results in a transient, developmental increase in cortical volume along with permanently altered cytoarchitecture, resembling observations in ASD. In this chapter, we test the hypothesis that a developmental decrease in cortical 5-HT in the first postnatal week, can alter cytokine production in cerebral cortex. This hypothesis is based on long-standing observations of mutual regulatory interactions between serotonin, cytokines and immune responses in the periphery. Our data show that production of several pro- and anti-inflammatory cytokines is decreased, on postnatal day seven, a week after the cortical 5-HT depletion, in mice that also display a significant decrease in social response. At the same age, neonatally 5-HT depleted mice display increased barrel field size in somatosensory cortex, a finding compatible with increased glia processes. Furthermore, GFAP staining indicates a delay of maturational change from glia fibers to multi-polar astrocytes. Our data suggest, that early postnatal 5-HT depletion of cortex may delay the maturation of glia cells and associated cytokine production and impair subsequent appropriate neural network formation and behavior. These results support the idea that altered cytokine profiles in the brain, as a consequence of 5-HT imbalances in some individuals with ASD, might be directly implicated in altered brain maturation and emergent, abnormal behavioral patterns. Altered cytokine production during development might also render the brain vulnerable for abnormal neuroinflammatory responses at later stages.
|Original language||English (US)|
|Title of host publication||Neuroinflammation|
|Subtitle of host publication||Pathogenesis, Mechanisms and Management|
|Publisher||Nova Science Publishers, Inc.|
|Number of pages||22|
|State||Published - Oct 1 2012|
ASJC Scopus subject areas