Deficient neuron-microglia signaling results in impaired functional brain connectivity and social behavior.
Microglia are phagocytic cells that infiltrate the brain during development and have a role in the elimination of synapses during brain maturation. Changes in microglial morphology and gene expression have been associated with neurodevelopmental disorders. However, it remains unknown whether these changes are a primary cause or a secondary consequence of neuronal deficits. Here we tested whether a primary deficit in microglia was sufficient to induce some autism-related behavioral and functional connectivity deficits. Mice lacking the chemokine receptor Cx3cr1 exhibit a transient reduction of microglia during the early postnatal period and a consequent deficit in synaptic pruning. We show that deficient synaptic pruning is associated with weak synaptic transmission, decreased functional brain connectivity, deficits in social interaction and increased repetitive-behavior phenotypes that have been previously associated with autism and other neurodevelopmental and neuropsychiatric disorders. These findings open the possibility that disruptions in microglia-mediated synaptic pruning could contribute to neurodevelopmental and neuropsychiatric disorders.
1] Mouse Biology Unit, European Molecular Biology Laboratory (EMBL), Monterotondo, Italy. [2].
Yang
Y
Zhan
1] Mouse Biology Unit, European Molecular Biology Laboratory (EMBL), Monterotondo, Italy. [2].
Rosa C
RC
Paolicelli
1] Center for Neuroscience and Cognitive Systems @UniTn, Istituto Italiano di Tecnologia (IIT), Rovereto, Italy. [2] Institutions Markets Technology (IMT) Institute for Advanced Studies, Lucca, Italy.
Francesco
F
Sforazzini
Mouse Biology Unit, European Molecular Biology Laboratory (EMBL), Monterotondo, Italy.
Laetitia
L
Weinhard
Mouse Biology Unit, European Molecular Biology Laboratory (EMBL), Monterotondo, Italy.
Giulia
G
Bolasco
Center for Life Nano Science, IIT, La Sapienza University, Rome, Italy.
Francesca
F
Pagani
Institute of Neuroinformatics, University of Zürich and Swiss Federal Institute of Technology (ETH), Zurich, Switzerland.
Alexei L
AL
Vyssotski
Center for Neuroscience and Cognitive Systems @UniTn, Istituto Italiano di Tecnologia (IIT), Rovereto, Italy.
Angelo
A
Bifone
Center for Neuroscience and Cognitive Systems @UniTn, Istituto Italiano di Tecnologia (IIT), Rovereto, Italy.
Alessandro
A
Gozzi
1] Department of Physiology and Pharmacology, La Sapienza University, Rome, Italy. [2] Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Neuromed, Pozzilli, Italy.
Davide
D
Ragozzino
Mouse Biology Unit, European Molecular Biology Laboratory (EMBL), Monterotondo, Italy.
Cornelius T
CT
Gross
D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D000073883:CX3C Chemokine Receptor 1; D063132:Connectome / Q000295:instrumentation / Q000379:methods*; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism / Q000473:pathology*; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D019707:Receptors, Chemokine / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D012919:Social Behavior; D013569:Synapses / Q000378:metabolism; D009435:Synaptic Transmission / Q000502:physiology*
D000073883:CX3C Chemokine Receptor 1; C471885:Cx3cr1 protein, mouse; D019707:Receptors, Chemokine