Link Between Impaired Synapse Clearance and Autism Uncovered

Recent research highlights a significant connection between the brain's ability to clear synapses and the development of autism spectrum disorder (ASD). Autism is a complex neurodevelopmental condition characterized by challenges in social interaction and communication, alongside repetitive behaviors and restricted interests. Scientific studies have increasingly suggested that irregularities in dendritic spines—tiny protrusions on nerve cells where synapses form—may be a hallmark of ASD. Notably, individuals with autism tend to have an excess of these spines, disrupting normal neural communication and potentially contributing to behavioral and cognitive differences.

Normal brain development involves a process called synaptic pruning, where unnecessary or weak synaptic connections are eliminated to refine neural networks. Microglia, the brain's resident immune cells, are central to this process—they help remove excess synapses, shaping healthy brain circuitry. However, understanding how microglia function in humans, especially those with autism, remains challenging because direct observation is limited.

To circumvent this, scientists used macrophages—immune cells derived from blood monocytes—as models to study microglial functions. These macrophages were differentiated into specific subtypes using colony-stimulating factors: GM-CSF, which induces a pro-inflammatory phenotype, and M-CSF, which promotes tissue repair activities. They then introduced synaptosomes—fragments of neuronal connections—from human induced pluripotent stem cells (hiPSCs). The findings revealed that macrophages from neurotypical individuals efficiently engulfed and cleared synaptosomes. In contrast, macrophages from individuals with ASD showed a marked reduction in this ability, especially those induced by M-CSF.

A key discovery was the reduced expression of the CD209 gene in ASD-derived macrophages, suggesting a molecular link to impaired phagocytosis. This impaired synaptic clearance could contribute to the excess of dendritic spines observed in ASD, highlighting a potential immune-related mechanism in the disorder's pathology.

This study provides the first evidence of disrupted synaptic pruning activity in human immune cells outside the brain, supporting the hypothesis that immune dysfunctions are involved in ASD. It opens new avenues for potential therapies aimed at restoring proper immune cell function. As Dr. Manabu Makinodan emphasizes, understanding these immune-synapse interactions could lead to more targeted drug development to address core symptoms of autism.

Overall, uncovering the role of peripheral immune cells in synaptic regulation enhances our grasp of ASD's neurobiological roots and points to promising directions for future interventions.

Source: https://medicalxpress.com/news/2025-04-compromised-synapse-ability-linked-autism.html