Abstract # 3149 Sex differences in the consequences of early-life immune activation on microglia-neural signaling and the ontogeny of hippocampal-dependent learning in the juvenile rat

Abstract

Developmental disorders associated with learning deficits, including Autism, have been linked to early-life immune activation, and notably, are male-biased. Microglia are the immune cells of the brain and are in constant communication with neurons, thus, microglia influence the function of surrounding neurons. Recent data indicate that microglia-neuron signaling is necessary for the proper formation of neural circuits during brain development. We determined that immune activation with lipopolysaccharide (LPS; 100ug/ml/kg) on postnatal day (P) 21 produces sex-dependent deficits in the emergence of hippocampal-dependent learning on P24 in rats. Gene expression analysis in the hippocampus at 2-, 4-, 8-, and 24-h following LPS showed sex differences in IL-1 β and IL-6 expression. Males, but not females, have a persistent decrease in BDNF expression starting 4hr post-LPS that persists until 24hr and an increase in C3 expression, an immune molecule that tags synapses for elimination, at 24hr. We are investigating whether we can rescue learning deficits by administering the microglia inhibitor minocycline at the time of LPS. We found a sex difference in the effectiveness of minocycline such that minocycline inhibits microglia in males, but is not as effective in females. Behavioral results following minocycline treatment will be discussed. Our data suggest that changes in microglia-neural communication following early-life immune activation are different in males and females, thus males and females may respond differently to therapies that target microglia.