Microglia, the innate immune cells of the central nervous system (CNS), respond rapidly and dynamically to homeostatic perturbations of the CNS milieu. In the healthy unperturbed brain, microglial processes make frequent contacts with neurons at synapses, impacting synaptic remodeling and turnover of dendritic spines. However, it remains unclear what receptors and signaling pathways govern microglial surveillance and synapse monitoring. Noradrenaline is a powerful signal that can affect many aspects of synaptic function and plasticity. Because microglia express high levels of ?2 adrenergic receptors (AR) compared to other cell types in the brain, we asked whether noradrenergic tone could alter microglial behavior with respect to synapses through ?2-AR signaling. Preliminary findings from our laboratory, along with published work, suggest that ?2-AR signaling inhibits microglial process motility and impairs experience-dependent plasticity in the visual cortex in mice. Based on this, I hypothesize that endogenous norepinephrine release alters microglial surveillance and microglia-synapse interactions through microglial ?2-AR signaling, leading to altered synaptic plasticity. To test this hypothesis, I will explore the effects of selectively ablating microglial ?2-AR signaling and altering endogenous norepinephrine release on microglial behavior and contributions to synaptic plasticity using the well-characterized model of ocular dominance plasticity during the visual critical period in mice. This study will be accomplished in three specific aims: I will investigate how both changes in norepinephrine and ablation of the ?2-A R in microglia impact ocular dominance plasticity (Aim 1). I will determine the effects of modulating endogenous norepinephrine pharmacologically and ablating microglial ?2-ARs on microglial physiology (Aim 2). Finally, I will investigate the effects of modulating noradrenergic tone on microglial interactions with synapses and synaptic remodeling (Aim 3). The results obtained from these complementary, but independent aims will greatly improve our understanding of the signaling mechanisms that govern microglial physiology and contributions to neural development and plasticity. Understanding the pathways that mediate microglial interactions with synapses will also provide novel therapeutic targets for neurodevelopmental and neurodegenerative disorders, where plasticity is affected.
Aberrations in structural modifications of neural circuits give rise to many neurological disorders such as autism, schizophrenia, and Alzheimer's disease. Understanding the underlying signaling mechanisms that govern nervous system circuit structure is essential for the development of therapeutics to treat these diseases. Here, I propose to study the role of microglia, the innate immune cell of the central nervous system, in the processes that underlie these circuit changes.
