Synaptic plasticity is critical for normal neurodevelopment and adult circuit function. Recent evidence suggests that microglia, classically studied in neuroinflammation, play critical roles in developmental synaptic plasticity. However, the mechanisms driving these roles are poorly understood. Purinergic signaling has been implicated in many neurodevelopmental processes, but studies on purinergic signaling in microglia have focused primarily on neuroinflammatory roles. It is unknown whether purinergic signaling contributes to the motility of non-inflamed microglia that underlies roles in synapse surveillance and plasticity. P2Y12 is a purinergic receptor associated with microglial motility and is highly expressed in resting, ramified microglia. However, P2Y12 is rapidly downregulated following inflammation, suggesting that it serves functions under healthy neurophysiological conditions. We propose that P2Y12 may be critical for basal microglial motility, synaptic surveillance, and synaptic plasticity. Using a mouse model, in Aim 1, we will determine whether genetic or pharmacological disruption of P2Y12 affects basal microglial morphology or motility in vivo.
In Aim 2, we will test whether P2Y12 disruption affects microglial synaptic surveillance and experience-dependent synaptic plasticity in the mouse visual system. In addition, P2Y12 has been implicated in a purinergic autocrine system in peripheral macrophage chemotaxis, suggesting that a similar mechanism may exist in microglia. Therefore in Aim 3, we will test whether microglial release of purines in an autocrine manner is necessary for efficient chemotaxis towards chemokines implicated in synaptic plasticity. Through these studies, we will explore novel roles for purinergic signaling in non-inflamed microglia.
Structural changes of synapses are a critical aspect of proper nervous system development and function. Disruptions in this process have been implicated in a variety of neurological disorders such as autism, Alzheimer's disease, and epilepsy. Understanding the mechanisms that drive synapse remodeling is key to developing therapeutics to treat these diseases. Here, we propose that purinergic signaling in microglia has novel roles in synapse remodeling, and may serve as an important factor in considering the neuroimmune interface.
|Sipe, G O; Lowery, R L; Tremblay, M-È et al. (2016) Microglial P2Y12 is necessary for synaptic plasticity in mouse visual cortex. Nat Commun 7:10905|