Cytokine Regulation of Secondary Neural Progenitors

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Maternal infection, allergies, autoimmune disease, obesity or pollution during pregnancy increase offspring risk for developing schizophrenia, ASD, ADHD, Tourette disorder and bipolar disorder by 2-4x. An unanswered question is what is enhancing the frequency of these disorders. Clinical studies have measured a 2-3 fold increase in IL-6 plasma levels in blood-spots from children who later develop neurodevelopmental disorders such as ASD. Other studies have shown that IL-6 is one of the few cytokines that is transported across the placenta and blood-brain barrier and that elevated early fetal levels of IL-6 are both necessary and sufficient to cause several behavioral phenotypes associated with neurodevelopmental disorders. However, studies are lacking to establish how IL-6 alters fetal brain development. Thus, this proposal seeks to investigate how IL-6 affects those human and mouse secondary neural progenitors that reside within the inner subventricular zone – a complex set of progenitors that have been understudied. Behavioral and physiological outcomes are highly dependent on the developmental timing of insults to the brain, which are directly related to the particular neural progenitors that are dividing, migrating and differentiating at specific developmental stages during fetal life. The majority of studies using animal models for ASD and schizophrenia have focused on the mouse correlate to the 12th week of human gestation where radial glial cells are the predominant neural progenitors. Our published data show that twice daily injections of IL-6 (that raise levels 2-fold over normal) from postnatal day 3 to 6 (correlating to 28-34 weeks of gestation in humans) leads to compromised performance on a variety of behavioral tasks. Most recently we have found that IL-6 specifically affects the proliferation of a subset of mouse SVZ neural progenitors, perturbing their proliferation and gene expression that reduces production of protoplasmic astrocytes and subcortical oligodendrocytes in several brain regions implicated in complex brain disorders. Thus, the central premise of this application is that systemically elevated IL-6 alters secondary neural progenitors to alter interneuron and macroglial genesis. Here we propose to generate human secondary neural progenitors from male and female iPSCs to determine how IL-6 alters their proliferation, specification and gene expression. Comparative studies will be performed on mouse SVZ cells. These comparative studies will enable us to catalog these human secondary neural progenitors. Furthermore, we will perform fate mapping analyses in mice treated with IL-6 at the stage of development corresponding to 24 weeks of human gestation to analyze histogenesis of the ventral striatum, amygdala and prefrontal cortex to more completely understand the histopathlogical orgins of complex neurodevelopmental disorders such as ASD. Our focus on modeling infections late in pregnancy, on aberrant interneuron genesis and macrogliogenesis will substantiate IL-6 as a key target for intervention to prevent psychiatric disorders.