A novel role for astrocyte-secreted synaptogenic factor Hevin/SPARCL1 in microglia-mediated synaptic pruning in response to visual experience

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ABSTRACT Synaptic circuits underlie behavior and cognition in higher animals. Proper establishment and maintenance of these circuits requires a balance in the number of connections formed and removed early in life. Increasing evidence suggests that impaired synapse formation and elimination contribute to the synaptic pathologies found in many neurological disorders. Rigorous in vitro and in vivo work from our lab and others have demonstrated the critical role for astrocytes and microglia in mediating synapse formation and elimination, respectively. Further work in the field has begun to describe how these two glial cell types may communicate to balance synapse formation and elimination. However, a detailed molecular understanding of the signals that mediate this communication and the role of such communication in circuit development have not been fully addressed. In my preliminary studies, I have identified the astrocyte-derived synaptogenic factor, Hevin/Sparcl1, as a direct signal to microglia. Hevin is proteolytically cleaved just after eye opening which coincides with a period of net decrease in thalamocortical synapse density. Additionally, Hevin’s C-terminal binds and activates TLR4 leading to an increase in the expression of microglia TLR2. Using a recently developed TLR2 knock in reporter line, I further show that TLR2 expression is restricted to microglia in the developing cortex and can be used to identify two populations of microglia, TLR2-low vs. TLR2-high. Intriguingly, I found that TLR2-high microglia have a high lysosomal compartment suggesting they represent a more phagocytic population of microglia. Based on these findings, this proposal will test the hypothesis that astrocyte secreted Hevin is cleaved in a sensory experience dependent manner to produce a C- terminal fragment that is required for synapse development. I further propose that Hevin signals locally through microglia expressed TLR4 to prime a subpopulation of the surrounding microglia to be more phagocytic marking them with an increased expression of TLR2. This hypothesis will be tested in two aims. Aim 1 will elucidate the role of Hevin proteolytic cleavage in synapse development and plasticity and link this event to sensory experience. Aim 2 will define a molecular mechanism that links processing of an astrocyte-derived synaptogenic factor with heightened microglia mediated synapse elimination. The findings from this study will for the first time identify a molecular signaling pathway from astrocytes to microglia that coordinates astrocyte and microglia function in response to sensory experience.