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

Autism Spectrum Disorder affects an estimated 1% of the global population, presenting a spectrum of social and cognitive challenges. Despite extensive research, the connection between genetic predispositions and the clinical manifestation of autism remains elusive. The study by Zhao and colleagues seeks to bridge this gap by scrutinizing the interplay between two neuronal proteins: MDGA2 and BDNF (Brain-Derived Neurotrophic Factor). They provide experimental evidence suggesting that an imbalance between these proteins may trigger the behavioral symptoms associated with ASD.

Central to their investigation is MDGA2, a protein known to facilitate nerve signal transmission. Researchers have previously linked genetic mutations in the MDGA2 gene to ASD cases in humans. This study’s critical finding was that mice engineered to express lower levels of MDGA2 exhibited behaviors reminiscent of autism, including repetitive grooming patterns and variations in social interaction. These behaviors underscore the profound impact of MDGA2 deficiency on neuronal function and highlight the necessity of maintaining a delicate equilibrium in neuronal signaling.

Furthermore, the researchers observed that the MDGA2-deficient mice displayed heightened excitability in nerve synapses, along with elevated levels of BDNF, a protein crucial for neuronal survival and growth. BDNF operates by binding to the TrkB receptor, triggering a cascade of cellular events essential for neuronal health. The experimental protocols utilized in the study involved administering an artificial peptide that mimicked MDGA2’s function, successfully inhibiting BDNF/TrkB signaling and resulting in a reduction of autism-like symptoms in the MDGA2-deficient mice.

Zhao and colleagues posited that MDGA2 and BDNF interact as counter-regulatory factors, vying for access to TrkB binding sites. This competition is vital for the regulation of excitatory neuronal activity. When either of these proteins is dysregulated, as seen in the MDGA2-deficient mice, a cascade of neurobiological repercussions can unfold, leading to the maladaptive behaviors characteristic of ASD. The findings suggest that restoring this balance may offer a new therapeutic strategy for treating autism-related symptoms.

The implication of these findings extends beyond laboratory settings; they offer a physiological framework for developing pharmacological interventions aimed at modulating MDGA2 and BDNF activities. As the authors reveal, further inquiries into the exact roles that MDGA2 and BDNF play in neuronal signaling could reshape the landscape of autism research. Understanding the balance between these proteins could pave the way for identifying specific biomarkers for ASD, thus enhancing diagnostic precision and treatment protocols.

Yun-wu Zhang, a co-author on the study, emphasized the importance of this work in elucidating the obscure relationship between MDGA2 mutations and the clinical phenotype of autism. By highlighting the anomalous activation of the BDNF/TrkB pathway in the face of MDGA2 deficiency, the study provides a clearer picture of how genetic factors can crystallize into observable behavioral phenotypes. The researchers stress that continuing research in this domain is critical for unlocking new therapeutic options for individuals living with autism.

Additionally, the research team’s findings represent an intersection of genetics and neurobiology, suggesting that addressing protein imbalances may hold the key to managing ASD symptoms. While the study focuses on a mouse model, the underlying principles may have significant implications for understanding ASD in humans, particularly with regard to personalized treatment plans predicated on genetic profiling and protein behavior.

As scientific inquiry continues to unveil the complexities of ASD, this study serves as a clarion call for further exploration into the molecular underpinnings of autism. The dynamic interplay between MDGA2 and BDNF not only holds the potential for therapeutic insights but also propels a deeper understanding of neuronal health and its influence on cognitive and behavioral outcomes.

The authors have robustly documented their methodologies, lending credence to their findings through rigorous experimental designs. Their work underscores the necessity of approaching autism research with a multi-faceted lens, where gene-protein interactions are scrutinized with the highest degree of scientific rigor. This progressive trajectory in autism research heralds a transformative era where nuances in protein-level interactions could unveil the most elusive aspects of ASD.

In summation, this research not only provides essential insights into the neurobiological bases of autism but also highlights an urgent need for innovative therapeutic strategies that can effectively address the challenges posed by this complex disorder. The implications of the findings resonate across various disciplines, mapping new territories for investigation and offering hope for improved outcomes for individuals impacted by autism.

In your coverage, please use this URL to provide access to the freely available paper in PLOS Biology: https://plos.io/4hJ3amN

Subject of Research: Animals
Article Title: Mdga2 deficiency leads to an aberrant activation of BDNF/TrkB signaling that underlies autism-relevant synaptic and behavioral changes in mice
News Publication Date: April 1, 2025
Web References: https://plos.io/4hJ3amN
References: Zhao D, Huo Y, Zheng N, Zhu X, Yang D, Zhou Y, et al. (2025) Mdga2 deficiency leads to an aberrant activation of BDNF/TrkB signaling that underlies autism-relevant synaptic and behavioral changes in mice. PLoS Biol 23(3): e3003047.
Image Credits: Credit: Dongdong Zhao, from Zhao D et al., 2025, PLOS Biology, CC-BY 4.0

Keywords: Autism Spectrum Disorder, MDGA2, BDNF, neuronal proteins, genetic factors, therapeutic targets, mouse model, excitatory activity, neurobiological mechanisms, research findings.