Microglia are versatile phagocytic cells that play an integral role in establishing mature neural networks. The
mechanisms whereby microglial cells (MGCs) respond to signals in their microenvironment to actively engulf
extraneous synapses are crucial for topographic map formation, excitatory-inhibitory balance, and synaptic
remodeling. MGC perturbation during early critical periods yields unrefined circuits with behavioral and social
impairments indicative of certain neurodevelopmental disorders, including autism. Among many activation
cues, neuronally-expressed fractalkine (CX3CL1) and complement (C1q, C3) proteins are key players for MGC
recruitment to, and active engulfment of underutilized synapses. Knockouts for these and/or their
corresponding microglial receptors (CX3CR1; CR3) compromise crosstalk necessary for MGC-mediated
synapse elimination. Such interactions have been implicated in shaping visual, somatosensory, and
hippocampal connections, but whether similar mechanisms also guide the maturation of auditory and
multisensory circuits remains in question. The midbrain inferior colliculus (IC) is an intriguing model structure
as its lateral cortex (LCIC) is organized into discrete zones that receive modality-specific inputs. Its modular-extramodular framework and interfacing projection patterns develop concurrently, emerging shortly after birth
and becoming well-defined by hearing onset. Initially diffuse and overlapping, somatosensory and auditory
inputs segregate as the LCIC matures, targeting complementary modular (GAD-positive) and extramodular
(calretinin-positive) domains, respectively. The present study aims: 1) to determine the spatiotemporal
patterning of MGCs and fractalkine/complement expression relative to emerging LCIC compartments, 2) to
assess fractalkine/complement involvement in sculpting distinct multisensory midbrain circuits, and 3) to test
if compromised MGC function during an early critical period of projection shaping results in atypical response
behaviors. The first objective utilizes immunocytochemical approaches in control and transgenic mice (GAD67-GFP, CX3CR1-GFP) to visualize MGCs and fractalkine/complement expression with respect to the emerging
LCIC microarchitecture, as well as testing if compromised signaling (CX3CR1GFP/GFP, C1qKO, C3KO, CR3KO)
alters modular-extramodular development. Proposed anterograde living slice experiments labeling auditory
and somatosensory afferents directly test microglial pruning/degradation of supranumerary LCIC synapses.
Finally, acoustic startle responses following auditory and/or somatosensory pre-pulse cues (i.e. pre-pulse
inhibition) will identify any multimodal psychophysical differences across strains. Project outcomes will
advance our understanding of microglial-neuronal signaling in the establishment of multimodal midbrain
compartments, their projection maps, and their behavioral significance. Further defining MGC influences
during critical periods of circuit assembly will inform how their dysfunction correlates with impaired
multisensory processing, communication difficulties, and other neurodevelopmental disorder etiologies.