It is becoming increasingly clear that glial cells play a crucial and dynamic role at the synapse during the critical period when neural circuits are formed and refined. The Stevens lab seeks to understand how neuron-glia communication facilitates the formation, elimination and plasticity of synapses—the points of communication between neurons—during both healthy development and disease.

A major goal of our lab is to elucidate the cellular and molecular mechanisms underlying activity-dependent synapse elimination during health and disease, with emphasis on the role of microglia and immune molecules in this process. Using the visual system as our primary model system, we employ a combination of live imaging, molecular, biochemical and neuroanatomical approaches.

In one line of investigation, we focuse on the role of neuron-glia-immune signaling in the patterning of neural circuits. We recently identified an unexpected role of glia and components of the innate immune system in synaptic pruning. We found that astrocytes promote neuronal expression of complement C1q, the initiating protein of the classical complement cascade. C1q binds to synapses and is required for synapse elimination in the developing visual system. As one of the primary roles of complement in the immune system is to mark unwanted cells or debris for removal, we hypothesize that C1q may be similarly “tagging” unwanted synapses for elimination in the brain. Importantly, we found that C1q becomes aberrantly upregulated and is relocalized to synapses at early stages of glaucoma and other neurodegenerative diseases suggesting a similar elimination mechanism may be in place.

Our current studies are aimed to define cellular and molecular mechanisms underlying complement dependent and independent synapse elimination during development and disease. Current research questions include: How are CNS synapses selectively targeted for elimination? Is complement-dependent synapse elimination an activity-dependent process? What is the role of astrocytes and microglia in synapse development and elimination?