Project Details
Description
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.
Status | Active |
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Effective start/end date | 9/6/23 → 8/31/25 |
Funding
- Eunice Kennedy Shriver National Institute of Child Health and Human Development: $431,750.00
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