Friday, May 9, 2025
5/9/2025
Roles of Calprotectin in a mouse model of maternal immune activation - Abstract Autism spectrum disorder (ASD) is a common neurodevelopmental disorder that currently lacks a fundamental approach to treatment. To develop an effective therapeutic strategy, we need to understand the molecular mechanism behind how ASD is established. It is known that infection during pregnancy increases the probability of offspring developing ASD; therefore, we have been using a maternal immune activation (MIA) model of ASD in mice. Using this model, we have found that the TLR3 ligand polyinosinic:polycytidylic acid (Poly(I:C)) as well as virus can pass through the placenta and directly activate fetal border-associated macrophages (BAMs) in the choroid plexus (CP) of the fetal brain. Furthermore, we have discovered that TLR3-MIA increases the number of BAMs in the CP as well as increases their expression of S100a8 and S100a9, which together forms a heterodimeric protein called calprotectin. Since increased calprotectin expression is known to associate with chronic inflammatory conditions, we hypothesize that calprotectin secreted from BAMs in the CP region may enhance inflammation in an autocrine manner and may also function in a paracrine manner to disrupt the differentiation, migration, and proliferation of neural progenitor cells (NPCs) in the periventricular area of the fetal brain. In this proposal, we will test our hypothesis by measuring calprotectin protein levels in the cerebrospinal fluid in response to TLR3-MIA by ELISA (Aim 1) and by investigating how calprotectin may influence NPC homeostasis in our TLR3-MIA model using single-nuclei RNA-seq (Aim 2). If our hypothesis is correct, this work will be a first step toward developing a therapeutic strategy for treating ASD by targeting calprotectin in the fetal brain.
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