Effects of early-life immune activation on microglia-mediated synapse remodeling and hippocampal-dependent learning in the juvenile rat
Date
2019
Authors
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Publisher
University of Delaware
Abstract
Dysregulation of the immune system during childhood leads to an increased risk for a number of neurodevelopmental disorders including autism spectrum disorders (ASD), attention deficit hyperactivity disorder (ADHD), and schizophrenia. Microglia are the primary immune cells of the brain and are in constant communication with surrounding neurons. As such, activation of microglia can significantly influence the function of these neurons. Throughout development, microglia-neuron communication and interactions are necessary for the proper formation of neural circuits which support the emergence and long-term maintenance of cognitive function (Paolicelli et al., 2011; Bilbo, 2010). We found that immune activation caused by administration of the bacterial cell wall component, lipopolysaccharide (LPS; 100ug/ml/kg), specifically on postnatal day (P) 21 produces deficits in the emergence of hippocampal-dependent learning days later, on P24, in male and female rats. Next, we examined gene expression in the hippocampus at 2-, 4-, 8-, and 24-hr following immune activation with LPS and determined that there is a robust response of the inflammatory molecules IL-1β and IL-6. Additionally, there is a decrease in brain derived neurotrophic factor (BDNF) expression. We found decreases in fractalkine Cx3xl1 expression, a chemokine that is produced by neurons and directly communicates with microglia, in both males and females 24hrs after LPS administration. We also found that males, but not females, have a significant increase in the expression of complement C3 at 24hr post-LPS administration. Therefore, we next examined whether LPS administration on P21 alters microglia phagocytosis of synapses in the hippocampus and whether measures of neuronal morphology and spine density were subsequently altered on P24, when we observed learning deficits. We found that LPS decreases microglia phagocytosis of the post-synaptic protein PSD95 in CA3 of males, and that this corresponds with an increase in spine density on basal dendrites in the CA3 of males on P24. Our data suggest that changes in microglia-neuron communication may underlie changes in hippocampal-dependent learning in the juvenile period of development. Changes in these unique microglial-neuronal interactions may be a key mechanism underlying the subsequent vulnerability to neurodevelopmental and learning disorders associated with early-life immune activation.
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Keywords
Cognition, Development, Early-life, Microglia