Mechanisms that regulate microglial dynamics in the context of plasticity

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Remodeling of cortical networks by visual experience during development relies on rapid changes in synaptic structure and function. The exquisite specificity of these activity-driven synaptic changes begs the question of how they are implemented. Surprisingly we have recently shown that microglia, the brain’s immune cells, are critical in this process. However, only a handful of the microglial mechanisms that contribute to plasticity have been described. These pathways were initially studied for their roles in neuroinflammatory responses and it is becoming clear that such mechanisms are also used in microglial function in the healthy brain. Norepinephrine signaling through microglial adrenergic receptors is known to affect microglial function in pathological settings but microglial contributions to norepinephrine’s effects on plasticity are as yet unstudied. Adrenergic signaling is a particularly intriguing candidate as it directly opposes the purinergic signaling pathway in microglia that we showed to be critical for plasticity, suggesting that adrenergic signaling in microglia could also impact synaptic remodeling. Additionally, adrenergic signaling modulates global state changes between sleep and wakefulness, and we have recently discovered that arousal changes microglial dynamics, which are critical to microglia- synapse interactions. Therefore, in this proposal we will test the hypothesis that norepinpehrine acting through microglial adrenergic receptors alters microglial function thereby affecting plasticity. To rigorously investigate how norepinephrine affects physiological microglia, we will first examine how adrenergic signaling affects microglial dynamics, surveillance and injury response in vivo (Aim1). We will then examine how adrenergic signaling in microglia affects activity-dependent plasticity in the visual cortex (Aim 2) and the associated functions of microglia during plasticity (Aim 3). We will use pharmacological approaches to alter adrenergic signaling while monitoring microglia and visual responses, and we will determine whether effects are specific to adrenergic signaling in microglia using conditional microglia-specific knock-out of the beta 2 adrenergic receptor (β2 AR) which is expressed at high levels within microglia. These studies will provide important insight into the molecular mechanisms used by microglia when interacting with synapses which is critical for understanding how microglia contribute to synaptic plasticity. Because synaptic plasticity is affected in a large number of neurodevelopmental and neurological disorders, many of which are also associated with aberrant adrenergic signaling, our work will provide potential targets for intervention to reinstate appropriate plastic changes and ameliorate symptoms in these diseases.