IL-1 beta alters cortical connectivity in development and disease through regulating synaptic localization of IL-1 beta receptors
Tuesday, Nov 12, 2013, 2:30 PM - 2:45 PM
++A.06.b. Synapse formation: CNS
, A. MCALLISTER;
UC Davis, Davis, CA
Autism spectrum disorder (ASD) appears to be caused by both genetic mutations and environmental factors, many of which alter synaptic function and/or the immune response. The pro-inflammatory cytokine IL-1β, in particular, has been implicated in ASD. IL-1β is elevated in the plasma and cerebrospinal fluid in ASD and polymorphisms in the IL-1 gene cluster, as well as mutations in an IL-1β receptor, IL1RAPL1, are linked to ASD (Young et al. 2011; Piton et al. 2008). During brain development, IL1RAPL1 and another IL-1β receptor, IL-1RAcP, function as central synaptic organizers through trans-synaptic interactions with PTPδ (Valnegri et al. 2011; Yoshida et al. 2011). Recently, our lab discovered that IL-1β levels are altered in the postnatal brain of offspring following maternal immune activation (MIA; Garay et al. 2012), which is a risk factor for ASD. These data suggest that IL-1β signaling might mediate the effects of the maternal peripheral immune response in altering connectivity and leading to ASD-like behaviors in offspring. We have started to test this hypothesis by assessing the effects of MIA and exogenous IL-1β on IL-1 receptor composition and synapse density in dissociated cortical cultures. We found that IL-1β and its receptors are present in the healthy, developing brain where it bi-directionally regulates cortical connectivity in a dose-dependent manner. Concentrations of IL-1β that decrease glutamatergic synapse density also decrease the synaptic localization of IL-1 receptors that act as synaptogenic molecules. Elevated levels of IL-1β caused by MIA also decrease synapse density and change IL-1 receptor localization, mimicking the effects of IL-1β on WT cultures. Together, these results suggest that environmental factors that alter IL-1β levels, and genetic mutations in IL-1 receptors, converge on the synaptic localization of IL-1 receptors as a central mechanism underlying aberrant cortical connectivity in ASD.
UC Davis Graduate Research Mentorship Fellowship (MLE)
Autism Speaks Dennis Weatherstone Predoctoral Fellowship (MLE)
R01-NS060125 from NINDS (AKM)
R01-MH088879 from NIMH (AKM)
UC Davis RISE Award (AKM)
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