Autism spectrum disorder (ASD) remains one of the most intricate neurodevelopmental conditions studied today, characterized by significant challenges in social communication and a repertoire of restricted, repetitive behaviors and interests. Despite extensive research, the underlying biological mechanisms that contribute to ASD have continued to evade full elucidation. Among the most compelling avenues of investigation is the role of synaptic connectivity and pruning within the developing brain—a process essential for the establishment and refinement of neural circuits that support cognitive and behavioral function. Recent pioneering research has now provided unprecedented insight into how immune cells outside the brain may contribute to synaptic abnormalities observed in ASD, hinting at novel pathological mechanisms and new therapeutic possibilities.
Neurons communicate across tiny specialized structures called synapses, which are housed on small protrusions known as dendritic spines. These spines serve as the microscopic platforms that facilitate neuronal connectivity. Intriguingly, individuals with ASD have been shown to possess an excess number of these dendritic spines, suggesting aberrant synaptic maintenance. Normally, the brain engages in a process called synaptic pruning during critical developmental windows, particularly in early childhood and adolescence. This essential remodeling removes redundant or weak synaptic connections, streamlining neural networks for optimal functioning. Microglia, the brain’s resident immune cells, have been identified as key players in this synaptic refinement, scavenging unnecessary synapses through phagocytosis.
While the role of microglia in healthy brain development has been studied in animal models, direct examination of these cells in humans—especially in those with ASD—has been hampered by significant ethical and technical constraints. To circumvent these obstacles, scientists recently turned their attention to peripheral immune cells that share some functional characteristics with microglia. Macrophages, derived from peripheral blood monocytes, offer a compelling model to probe immune-related synaptic clearance outside the confines of the central nervous system. This innovative approach has propelled understanding beyond previous limitations, serving as a window into neuroimmune interactions implicated in ASD.
In a groundbreaking experimental study, researchers differentiated monocyte-derived macrophages into two major phenotypes by employing specific colony-stimulating factors. Granulocyte-macrophage colony-stimulating factor (GM-CSF) prompted a pro-inflammatory “M1-like” macrophage subtype, while macrophage colony-stimulating factor (M-CSF) generated an “M2-like” phenotype associated with tissue repair and immune regulation. The functional capacity of these macrophages to engulf synaptic components was assessed using synaptosomes—isolated fragments of synaptic terminals—produced from induced pluripotent stem cell (iPSC) derived neurons. This approach utilized cutting-edge stem cell technology to recreate human synaptic material with high fidelity, enabling precise measurement of synaptic phagocytosis in vitro.
Results from this study revealed a profound distinction between macrophage subtypes and their phagocytic capabilities. M-CSF-induced macrophages from neurotypical individuals demonstrated robust engulfment of synaptosomes, reflecting a functional synaptic clearance mechanism reminiscent of microglial activity. In stark contrast, macrophages derived from individuals with ASD displayed a significant reduction in this phagocytic ability, particularly within the M-CSF-induced subset. This diminished synaptic clearance points to a peripheral immune dysfunction that could mirror or contribute to the synaptic pruning deficits observed in the autistic brain.
At the molecular level, this impaired phagocytosis correlated with decreased expression of the CD209 gene, which encodes a pattern recognition receptor implicated in the binding and internalization of glycosylated ligands, including synaptic proteins. The downregulation of CD209 may compromise the macrophages’ capacity to recognize and ingest synaptic elements effectively, potentially leading to the persistence of excess synaptic connections. Such a mechanism aligns with the prevailing hypothesis that disrupted synaptic pruning contributes centrally to ASD pathophysiology by sustaining aberrant circuit connectivity and brain network hyperexcitability.
This revelation marks a significant advance in understanding how systemic immune cells interface with neural substrates in ASD. By documenting a specific functional impairment in macrophage-mediated synaptic phagocytosis outside the brain, the study suggests that neuroimmune dysregulation in autism transcends the central nervous system and is detectably manifested in peripheral immune compartments. This paradigm shift opens the door to new biomarkers and therapeutic targets that leverage peripheral immune cells as accessible proxies for brain microglial function.
Dr. Michihiro Toritsuka, senior author and psychiatrist-scientist at Fujita Health University, emphasized the novelty of the findings, stating, “This study is the first to reveal lower phagocytosis capacity of synaptosomes in ASD-M-CSF macrophages compared to typically developed-M-CSF macrophages, with a correlation to CD209 gene expression.” His team’s work carefully integrates psychiatric expertise with cellular and molecular neurobiology, deploying an innovative translational model system to bridge laboratory discoveries and clinical relevance.
Moreover, Professor Manabu Makinodan, co-corresponding author, highlighted the potential clinical implications of this research. If similar impairments in synaptic phagocytosis and CD209 expression are confirmed within brain-resident microglia of individuals with autism, targeted therapies aimed at restoring or enhancing phagocytic function might emerge as viable strategies to address core ASD symptoms. Such treatments could complement existing behavioral and pharmacological interventions, offering a mechanistic approach anchored in the biology of neuroimmune interaction.
Beyond its immediate impacts on autism research, this study challenges traditional views that confine synaptic pruning pathology strictly to the brain’s immune milieu. By demonstrating that peripheral macrophages also display dysfunctional synaptic clearance, the research raises critical questions about the systemic nature of immune contributions to neurodevelopmental disorders. It also underscores the utility of iPSC-derived cellular models in simulating complex human brain phenomena, particularly when direct brain tissue access is impractical or impossible.
Taken together, these findings not only expand the scientific understanding of ASD’s etiology but also highlight a novel immune-synapse interface that could redefine diagnostic and therapeutic frameworks. As the field moves forward, further investigations will be needed to dissect the signaling pathways regulating CD209 expression and macrophage function, as well as to explore whether modulation of these pathways can lead to measurable improvements in synaptic architecture and behavioral outcomes in ASD.
In conclusion, this research marks a milestone in autism neuroscience by linking impaired macrophage-mediated synaptosome phagocytosis with molecular alterations in CD209 gene expression. It emphasizes the significance of immune system contributions outside the brain and fosters hope for innovative avenues of intervention rooted in neuroimmune biology. As the intricate dance between neurons and immune cells becomes increasingly illuminated, the possibility of correcting synaptic imbalances associated with ASD through immune modulation grows increasingly tangible.
Subject of Research: People
Article Title: Impaired synaptosome phagocytosis in macrophages of individuals with autism spectrum disorder
News Publication Date: 4-Apr-2025
References: DOI: 10.1038/s41380-025-03002-3
Image Credits: Credit: Michihiro Toritsuka from Fujita Health University School of Medicine, Japan
Keywords: Autism spectrum disorder, synaptic pruning, macrophages, microglia, phagocytosis, CD209, synaptosomes, neuroimmune interaction, induced pluripotent stem cells, neurodevelopment, synaptic clearance, neurobiology
