TY - JOUR
T1 - Cytoskeletal control in adult microglia is essential to restore neurodevelopmental synaptic and cognitive deficits
AU - Kessels, Sofie
AU - Trippaers, Chloë
AU - Mertens, Melanie
AU - Hamad, Ibrahim
AU - Rombaut, Ben
AU - Janssen, Art
AU - Ramanathan, Keerthana
AU - Duwé, Sam
AU - Gharghani, Adelaïde M.
AU - Theuwis, Rune
AU - Delbroek, Amber
AU - Vangansewinkel, Tim
AU - Berden, Lisa
AU - Beeken, Jolien
AU - Vandormael, Patrick
AU - Poovathingal, Suresh
AU - Voets, Thomas
AU - Kleinewietfeld, Markus
AU - Nguyen, Laurent
AU - Antel, Jack P.
AU - Healy, Luke M.
AU - Cowley, Sally A.
AU - Ishizuka, Koko
AU - Rigo, Jean Michel
AU - Hendrix, Jelle
AU - Vanmierlo, Tim
AU - Dewachter, Ilse
AU - Alpizar, Yeranddy A.
AU - Sawa, Akira
AU - Brône, Bert
N1 - Publisher Copyright:
Copyright © 2025 The Authors.
PY - 2025/8/29
Y1 - 2025/8/29
N2 - Synaptic dysfunction is a hallmark of neurodevelopmental disorders (NDDs), often linked to genes involved in cytoskeletal regulation. While the role of these genes has been extensively studied in neurons, microglial functions such as phagocytosis are also dependent on cytoskeletal dynamics. We demonstrate that disturbance of actin cytoskeletal regulation in microglia, modeled by genetically impairing the scaffold protein Disrupted-in-Schizophrenia 1 (DISC1), which integrates actin-binding proteins, causes a shift in actin regulatory balance favoring filopodial versus lamellipodial actin organization. The resulting microglia-specific dysregulation of actin dynamics leads to excessive uptake of synaptic proteins. Genetically engineered DISC1-deficient mice show diminished hippocampal excitatory transmission and associated spatial memory deficits. Reintroducing wild-type microglia-like cells via bone marrow transplantation in adult DISC1-deficient mice restores the synaptic function of neurons and rescues cognitive performance. These findings reveal a pivotal role for microglial actin cytoskeletal remodeling in preserving synaptic integrity and cognitive health. Targeting microglial cytoskeletal dynamics may effectively address cognitive impairments associated with NDDs, even in adulthood.
AB - Synaptic dysfunction is a hallmark of neurodevelopmental disorders (NDDs), often linked to genes involved in cytoskeletal regulation. While the role of these genes has been extensively studied in neurons, microglial functions such as phagocytosis are also dependent on cytoskeletal dynamics. We demonstrate that disturbance of actin cytoskeletal regulation in microglia, modeled by genetically impairing the scaffold protein Disrupted-in-Schizophrenia 1 (DISC1), which integrates actin-binding proteins, causes a shift in actin regulatory balance favoring filopodial versus lamellipodial actin organization. The resulting microglia-specific dysregulation of actin dynamics leads to excessive uptake of synaptic proteins. Genetically engineered DISC1-deficient mice show diminished hippocampal excitatory transmission and associated spatial memory deficits. Reintroducing wild-type microglia-like cells via bone marrow transplantation in adult DISC1-deficient mice restores the synaptic function of neurons and rescues cognitive performance. These findings reveal a pivotal role for microglial actin cytoskeletal remodeling in preserving synaptic integrity and cognitive health. Targeting microglial cytoskeletal dynamics may effectively address cognitive impairments associated with NDDs, even in adulthood.
KW - Neuron morphology
KW - Brain development
KW - Neurodevelopmental disorders (NDDs)
UR - https://www.scopus.com/pages/publications/105014914387
U2 - 10.1126/sciadv.adw0128
DO - 10.1126/sciadv.adw0128
M3 - Article
C2 - 40880479
AN - SCOPUS:105014914387
SN - 2375-2548
VL - 11
JO - Science Advances
JF - Science Advances
IS - 35
M1 - eadw0128
ER -