Synaptic Pruning Deficits in Autism Tied to Immune Cell Dysfunction
The study finds that impaired immune cell function contributes to synaptic pruning deficits in autism.
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Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by challenges in social communication and the presence of restricted and repetitive behaviors. One notable feature in individuals with ASD is the presence of an increased number of dendritic spines, tiny protrusions on neurons where synapses are formed. This overabundance of spines suggests a disruption in the normal functioning of the brain, which could contribute to the cognitive and behavioral traits observed in ASD.
Dendritic spines
Tiny protrusions on neurons where synapses form. Abnormalities in these spines are thought to contribute to neurodevelopmental disorders like ASD.
Synaptic pruning and the role of microglia
Typically, during brain development, synaptic pruning occurs, where excess or weak synaptic connections are eliminated to make way for more efficient neural networks. This process is essential in early development and adolescence. Microglia, the brain's resident immune cells, are critical to pruning. They help by removing unnecessary synapses, thereby facilitating the formation of healthy neural circuits. However, studying microglial function in human brains – particularly in individuals with autism – has proven challenging due to technical and ethical barriers.
Synaptic pruning
The process through which unnecessary or weak synaptic connections are eliminated during brain development to enhance neural efficiency.
Microglia
Resident immune cells in the brain that help regulate synaptic pruning by removing excess synapses.
Using macrophages to study immune functions in ASD
To overcome these obstacles, researchers utilized macrophages, immune cells derived from blood monocytes, as substitutes for brain microglia. These macrophages were differentiated into two subtypes using specific colony-stimulating factors (CSFs): GM-CSF, which induced a pro-inflammatory phenotype (M1-like), and M-CSF, which promoted a phenotype associated with immune regulation and tissue repair (M2-like). The study aimed to explore the macrophages' ability to clear synaptic material. For this purpose, synaptosomes – fragments of neuronal connections – were generated from human induced pluripotent stem cells (hiPSCs).
Macrophages
A type of immune cell that engulfs and digests cellular debris, foreign substances and pathogens.
Findings of impaired synaptic phagocytosis in ASD macrophages
The results revealed that M-CSF-induced macrophages (M-CSF MΦ) from typically developing individuals were more efficient in phagocytosis – engulfing and clearing synaptosomes – compared to GM-CSF-induced macrophages. However, macrophages derived from individuals with ASD showed a marked reduction in their phagocytic capacity. This impairment was linked to lower expression levels of the CD209 gene, which is believed to play a key role in macrophages' ability to clear synaptic proteins.
Phagocytosis
The process by which cells, such as macrophages, engulf and digest foreign particles or dead cells.
CD209 gene
A gene involved in the function of immune cells, particularly their ability to clear synaptic material.
These findings suggest that dysfunctional phagocytosis may contribute to the synaptic pruning deficits seen in ASD. The CD209 gene might serve as a molecular mediator in this process, providing new insights into the role of immune cells in synapse elimination.
Implications of immune dysfunction in ASD
This research provides the first direct evidence of impaired synaptic pruning activity in human immune cells outside the brain. Previous studies in postmortem tissue and brain imaging have suggested that ASD brains exhibit increased dendritic spine density and hyperconnectivity. The current findings add to the growing body of evidence implicating immune dysfunction in the neurodevelopmental alterations associated with ASD.
“If the decreased phagocytosis capacity of synaptosomes and decreased CD209 expression are similarly identified in the microglia of individuals with ASD in future studies, it may lead to more effective drug discovery targeting core symptoms of ASD.”
Dr. Manabu Makinodan
This research opens a new avenue for understanding how immune cells influence synapse elimination, which could inform the development of treatments aimed at restoring phagocytic function.
By demonstrating impaired macrophage function associated with ASD, this study underscores the importance of immune-synapse interactions in the condition. These findings not only expand our understanding of ASD but also point to potential therapeutic strategies that could help address the underlying synaptic pruning defects in individuals with autism.
Reference: Nishi Y, Toritsuka M, Takada R, et al. Impaired synaptosome phagocytosis in macrophages of individuals with autism spectrum disorder. Mol Psychiatry. 2025. doi: 10.1038/s41380-025-03002-3
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