Investigating the Role of Glia in Activity-Dependent Synapse Elimination

Boston Children'S Hospital, Boston MA

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): The formation of mature neural circuits requires selective pruning of inappropriate synapses and strengthening of appropriate synaptic connections. A longstanding question in neurobiology is what determines which synapses will be eliminated? While the role of spontaneous and experience-driven synaptic activity in developmental synaptic pruning is well established, surprisingly little is known about the molecules and mechanisms that link neural activity with the physical elimination of specific synapses. Our recent studies reveal that glial cells-microglia and astrocytes--are key players in developmental synaptic pruning. We discovered that C1q, the initiating protein of the classical complement cascade, is significantly upregulated in developing neurons by immature astrocytes. Both C1q and downstream C3 are moreover localized to synapses and are required for developmental synapse elimination in the visual system; however the mechanisms by which complement mediates synaptic pruning are completely unknown. The primary role of the complement cascade in the innate immune system is to opsonize or tag unwanted cells or debris for removal by phagocytic macrophages via specific complement receptors. Our preliminary studies support a model in which inappropriate synapses in the developing brain are similarly tagged by complement and then eliminated by microglia, the primary phagocytic cells in CNS. Given the importance of neural activity in synaptic pruning, a major goal of the proposed research is to determine whether and how the complement system cooperates with neuronal activity to give rise to precise visual circuit wiring. Activity-dependent competition between neighboring axons is thought to drive the elimination of weak synaptic inputs; however, the molecular mechanisms remain elusive. We propose a model in which activity and astrocyte-derived factor(s) act cooperatively to upregulate C1q in developing neurons which leads to local activation of the complement cascade at neighboring weak synapses and the elimination of complement (C3) tagged synapses by microglia. We will use the mouse retinogeniculate system as a model to manipulate neural activity at specific synapses in vivo to examine the role of microglia (Aim 1), C1q and C3 (Aim 2) and astrocytes (Aim 3) in activity-dependent synapse elimination. Specifically, we will ask: 1) Does complement specifically tag weak synapses for elimination? 2) Do microglia actively prune synapses or engulf synapses already undergoing elimination? 3) Does neuronal activity regulate the complement cascade, and if so, how? The answers to these questions will add to our understanding of the role of microglia and the complement cascade in developmental synapse elimination, and may ultimately provide new insight into how CNS synapses are eliminated during normal brain wiring, and possibly in diseases involving aberrant synapse loss and synaptic connectivity, such as epilepsy and autism.