Research

Our laboratory 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 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.

UNEXPECTED ROLE OF INNATE IMMUNE PROTEINS IN CNS SYNAPSE ELIMINATION

Immune molecules in the healthy brain? Until recently the healthy brain was largely thought to be an immune privileged site. This view has shifted dramatically with the growing realization that the nervous and immune systems interact on many levels in health and disease.

We and our collaborators have identified an unexpected role for glia and components of the classical complement cascade in developmental synaptic pruning. The primary role of the complement cascade in the immune system is to opsonize or tag unwanted cells or debris, which are then eliminated by phagocytic macrophages. We found that C1q and downstream complement protein, C3,  target immature synapses and are required for synapse elimination in the developing visual system (Stevens et al., Cell 2007).

The Retinogeniculate System

Classical complement cascade proteins mediate synaptic refinement in the developing retinogeniculate system. We look specifically at eye-specific segregation and optic crush models.

One current goal is to understand how synapses in the CNS are selectively targeted for elimination by complement and other mechanisms. Why does one synapse get eliminated while a nearby synapse stays intact?

MICROGLIA PRUNE DEVELOPING SYNAPSES

Immune molecules in the healthy brain? Until recently the healthy brain was largely thought to be an immune privileged site. This view has shifted dramatically with the growing realization that the nervous and immune systems interact on many levels in health and disease.

We and our collaborators have identified an unexpected role for glia and components of

the classical complement cascade in developmental synaptic pruning. The primary role of the complement cascade in the immune

system is to opsonize or tag unwanted cells or 

debris, which are then eliminated by phagocytic macrophages. We found that C1q and downstream complement protein, C3, target immature synapses and are required for synapse elimination in the developing visual system (Stevens et al., Cell 2007).

The complement punishment model of synaptic elimination in the developing visual system

HOW ARE SYNAPSES ELIMINATED IN DISEASE?

Another major goal is to understand the signals that regulate the complement expression and function. We found that an astrocyte-derived factor (Factor X) up regulates C1q in developing retinal neurons during synapse elimination. Moreover, a dramatic up-regulation of complement occurs in glaucoma, Alzheimer’s, and other CNS diseases concurrently with the appearance of reactive astrocytes and microglia  (Howell et al., JCI 2011) (Stephan et al., Annu. Rev. Neurosci. 2012).

Although synapse elimination is largely considered a developmental process, early synapse loss and dysfunction are becoming increasingly recognized as a hallmark of many CNS neurodegenerative diseases; however the factors that trigger synapse loss in the aged and diseased brain remain elusive.

 

We hypothesize  that synapse loss in CNS neurodegenerative diseases is caused by a reactivation, in the mature brain, of similar developmental mechanisms of synapse elimination.  Indeed, components of the complement cascade are profoundly up-regulated in Alzheimer’s Disease, glaucoma, and other brain diseases and are localized to synapses prior to signs of neuronal loss in animal models of neurodegenerative disease

In addition to our interest in CNS neurodegenerative diseases, we are probing the potential link between complement proteins and synapse loss in the pathogenesis of epilepsy and neurodevelopmental disorders.

Complement-mediated synapse elimination during development and in neurodegenerative diseases.

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The Stevens Lab