Retooling innate immunity: An investigation of TLR-mediated glial priming across lifespan

This proposal examines how a novel TLR glial signaling pathway drives phagocytic competence in
glia, and defines its function in pruning neuronal number and connectivity across lifespan. Glia
provide an extensive support system for healthy neurons by promoting their survival, connectivity,
and synaptic function. Remarkably, glia can rapidly switch roles to precisely eliminate dying neurons
or unwanted neurites/synapses by phagocytosis. These diametrically opposed functions necessitate
fail-safe signaling mechanisms between neurons and glia; yet hese crucial regulatory mechanisms
have remained largely obscure. Toll-like receptor (TLR) pathways were first identified for their roles in
embryonic patterning and have since been defined as a conserved centerpiece of innate immunity.
Our lab made the unexpected discovery that one of the most pronounced phenotypes associated with
loss of a Drosophila TLR, a dramatic increase in the number of apoptotic neurons during
development, is caused by selective loss of the TLR in glia. We demonstrated that release of the TLR
ligand from dying neurons activates a novel TLR pathway in glia to drive phagocytic competence.
In this proposal we build on our novel preliminary findings to establish how this pathway regulates the
speed and specificity of debris clearance, and define its roles in neuron-glia interactions in synapse,
neurite, and neuron removal across lifespan. Our unifying hypothesis is that non-canonical TLR
signaling underlies the speed and specificity of debris clearance critical for proper CNS development
and function. In the first aim, we focus on elucidating how glia are transformed into phagocytes during
development by defining how information is relayed through the TLR pathway to elucidate how glia
are primed to become phagocytic. In the second aim, we seek to extend our published work to
investigate whether TLR signaling is a widespread early detection system to alert glia to the presence
of neuronal debris. And in the third aim, we examine the function of TLR signaling in sculpting circuits
in the olfactory system based on our preliminary findings that glial TLR signaling constrains synapse
number in this well defined circuit. Here we propose to leverage the fly olfactory circuit as a model for
defining glial phagocytic function in synapse maintenance. Together, these studies will shed critical
light on the early signaling interactions between glia and their phagocytic substrates essential for
brain health across lifespan.

Grant Number: 5R01NS120689-05
NIH Institute/Center: NIH
Principal Investigator: Heather Broihier