Immune Regulation of Neural Stem/Progenitors

Rutgers University

Project Description

A considerable number of studies have highlighted the connection between
infections during pregnancy and increased risk for autism leading to the view
that maternal immune activation, is a significant contributor to autism spectrum
disorders (ASD) incidence. Epidemiological studies indicate that the risk for
ASD is greatest when infections occur in the early third trimester. Cytokines
produced maternally after infection can cross the placenta to affect the
developing brain. However, it is not clear how these cytokines alter the
trajectory of neural development.

The brain develops from two sets of neural stem cells known as the primary and secondary neuroepithelial. By the early third trimester, most of the primary neuroepithelial cells have matured with large numbers of secondary neuroepithelial cells present. Oddly, most autism
studies using animal models have produced maternal immune activation during the
mouse equivalent of the 1st trimester. In our studies on the secondary neuroepithelial cells that reside in the subventricular zone (SVZ) and the subgranular zone of the hippocampus we have established that one of the key cytokines implicated in ASD, interleukin-6 (IL-6), has opposite effects on these two cell populations - it enhances cell production from the SVZ whereas it
inhibits cell production in the SGZ. These published data lead to our overall hypothesis that elevated levels of IL-6 in the immature brain will alter brain development by affecting the output of the neural stem/progenitors that reside in 4 late developing regions of the brain: the forebrain, hippocampus, cerebellum and the hypothalamus.

To test this hypothesis, we will first perform cell culture studies to determine how IL-6 affects the growth of these secondary neuroepithelial cells. Then, to establish how elevated levels of IL-6 affect the secondary neuroepithelial cells in vivo, we will develop a new model of ASD
where we will inject postnatal day 1-4 mouse pups (representing gestational
weeks 24-34 in the human) with IL-6 and study the growth and development of
these progenitors. We will establish whether both neurogenesis and gliogenesis
are altered. In addition, we will subject the mice to a battery of behavioral
tasks to assess learning, memory, anxiety and social interactions. Finally, we
will initiate studies to establish how elevating IL-6 affects the development of
the gastrointestinal system. Upon completing these experiments we will have
established a new mouse model for ASD and we will have obtained new insights
into the modes through which IL-6 affects brain and gastrointestinal system
development. The data obtained from these studies will lend additional support
for the therapeutic neutralization of IL-6 in premature and neonatal infants at
risk for developing ASD.




Selection Criteria

Title Hits Shared With Upload Date Member
No Recruitment resources
Title Hits Shared With Upload Date Member
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Team Members

Steven Levison
Principal Investigator
steve.levison@rutgers.edu
(973) 972-5162

Contact Info

steve.levison@rutgers.edu.
(973) 972-5162
Cancer Research Center (CANCT) 195 South Orange Avenue Room H-1226
Newark, NJ 07103

Links

Rutgers University