The effects of early-life immune activation on microglia-mediated neuronal remodeling and the associated ontogeny of hippocampal-dependent learning in juvenile rats

Abstract

Many neurodevelopmental disorders and associated learning deficits have been linked to early-life immune activation or ongoing immune dysregulation (Laskaris et al., 2016; O'Connor et al., 2014; Frick et al., 2013). Neuroscientists have begun to understand how the maturation of neural circuits allows for the emergence of cognitive and learning behaviors; yet we know very little about how these developing neural circuits are perturbed by certain events, including risk-factors such as early-life immune activation and immune dysregulation. To answer these questions, we examined the impact of early-life immune activation on the emergence of hippocampal-dependent learning in juvenile male and female rats using a well-characterized hippocampal-dependent learning task and we investigated the corresponding, dynamic multicellular interactions in the hippocampus that may contribute to these learning deficits. We found that even low levels of immune activation can result in hippocampal-depedent learning deficits days later, but only when this activation occurs during a sensitive period of development. The initial immune response and associated cytokine production in the hippocampus resolved within 24 h, several days prior to the observed learning deficit, but notably the initial immune response was followed by altered microglial-neuronal communication and synapse remodeling that changed the structure of hippocampal neurons during this period of juvenile brain development. We conclude that immune activation or dysregulation during a sensitive period of hippocampal development can precipitate the emergence of learning deficits via a multi-cellular process that may be initiated by, but not the direct result of the initial cytokine response. SIGNIFICANCE STATEMENT: Many neurodevelopmental disorders have been linked to early-life immune activation or immune dysregulation; however, very little is known about how dynamic changes in neuroimmune cells mediate the transition from normal brain function to the early stages of cognitive disorders, or how changes in immune signaling are subsequently integrated into developing neuronal networks. The current experiments examined the consequences of immune activation on the cellular and molecular changes that accompany the emergence of learning deficits during a sensitive period of hippocampal development. These findings have the potential to significantly advance our understanding of how early-life immune activation or dysregulation can result in the emergence of cognitive and learning deficits that are the largest source of years lived with disability in humans.

Keywords: Cytokines; Development; Hippocampus; Learning deficits; Microglia; Sensitive period; Synapse remodeling.