# Control of microglial dynamics by the Arp2/3 complex and the autism- and schizophrenia-associated protein CYFIP1

## TL;DR

This study shows how the Arp2/3 complex and CYFIP1 protein control microglial structure and function, which may relate to neuropsychiatric disorders.

## Contribution

The study reveals a novel role for CYFIP1 and the Arp2/3 complex in regulating microglial dynamics and phagocytic activity.

## Key findings

- CYFIP1 and the Arp2/3 complex are essential for maintaining microglial morphology and surveillance.
- Cyfip1 deletion increases lysosomal cargo and synaptic engulfment in microglia.
- These findings suggest a shift in microglial function toward heightened phagocytic processing.

## Abstract

Microglia, the resident immune cells of the brain, continuously survey their environment using a highly dynamic network of branched processes. Altered microglial morphology and behavior are increasingly linked to neurodevelopmental and neuropsychiatric disorders, yet the cytoskeletal mechanisms that generate and maintain ramified microglial structure remain unclear. We identify a crucial role for actin cytoskeleton remodeling via the Arp2/3 complex and the schizophrenia-associated regulator CYFIP1 in sustaining complex microglial morphology and effective surveillance of the brain. Cyfip1 deletion also increases synaptic cargo within microglial lysosomes, indicating a shift toward heightened phagocytic processing. These findings reveal cell-autonomous roles for CYFIP1 and Arp2/3-driven actin remodeling that may underlie microglial contributions to neuropsychiatric disease.

Microglia use a highly complex and dynamic network of branched processes to sense and respond to their surroundings. Despite emerging evidence that microglial motility plays important roles in brain development, neurodegeneration, and neuropsychiatric disease, little is known about the intracellular machinery orchestrating microglial process dynamics. Here, we identify roles for regulators of the actin cytoskeleton in controlling microglial behavior. We show that the actin branching Arp2/3 complex is critical for maintaining microglial morphology and is required for surveillance but not chemotactic motility. Neuropsychiatric disease-associated CYFIP1, a core component of the WAVE regulatory complex linking upstream signaling pathways to activation of the Arp2/3 complex, is highly expressed in microglia but has an unknown function. We report that conditional deletion of Cyfip1 in mouse microglia reduces their morphological complexity and surveillance of the brain parenchyma, with no effect on chemotaxis. Deletion of Cyfip1 also increased microglial CD68 positive lysosome volume and engulfment of presynapses. Thus, actin remodeling by CYFIP1 and the Arp2/3 complex controls microglial dynamics and shifts microglia away from a homeostatic state with potential implications for neuropsychiatric disease.