When the Brain Reorganizes: The Role of Early Neural Cleanup and Inflammation in Autism

Daniele Stajano, PhD

“The developing brain progresses by eliminating excess connections and stabilizing the useful ones” — Jean-Pierre Changeux

The human brain is a dense and vibrant network of neurons connected each other through special junctions called synapses, forming a landscape that works like a living city. During early childhood, this city grows rapidly. Synapses multiply far beyond what is needed, creating an abundance of possible roads for information to travel. Later, the brain refines this excess through a process called synaptic pruning, a careful trimming that preserves only the most useful connections.
When this pruning is disrupted, communication between neurons becomes messy or inefficient. This imbalance is thought to play a role in Autism Spectrum Disorder (ASD), where neural networks struggle to maintain a coherent flow of information.

Autism as a Developing Puzzle

ASD is a neurodevelopmental pathology affecting social interaction and involving repetitive behaviors. In Europe, around 1 in 100 children receives a diagnosis. Its causes remain complex, involving both genetics and environmental factors such as parental age, maternal nutrition, infections during pregnancy, and prematurity. Recent studies also reveal roles for the immune system and metabolism in ASD.

The Immune System’s Hand in Brain Wiring: The Role of Microglia

Microglia, the brain’s resident immune cells, normally shape development by pruning synapses, selecting which connections to strengthen and which to remove. In ASD, microglia often appear overactive, potentially causing excessive pruning or inflammatory stress. Prenatal immune challenges, including viral infections, may also reroute fetal brain development by activating microglia too early or too strongly.
Growing evidence shows a strong link between inflammation and ASD.
Neuroinflammation, marked by increased microglia activity, has been observed in autistic individuals and animal model, where high levels of inflammatory molecules like TNF-α and IL-6 are often found in the blood and cerebrospinal fluid.
When inflammation is altered during critical developmental windows, it may disturb synaptic pruning. In fact, excessive immune activity can remove useful synapses, while insufficient allows unhelpful ones to remain. Maternal immune activation during pregnancy, sparked by infections or inflammation, has also been associated with increased ASD risk and altered neural circuitry in offspring.
The gut–brain axis also enters the picture. Many autistic individuals experience gastrointestinal issues, which may relate to microbial imbalances that trigger inflammation and immune dysfunction.

Searching for New Pathways

If neuroinflammation is related to autism, researchers are exploring treatments, such as therapies based on immunoglobulins, aimed at reducing it and potentially relieving behavioral and cognitive symptoms in some individuals. Genetic studies are identifying key mutations and pathways that could guide personalized therapies in the future.
The gut microbiome is gaining attention as well. Probiotics, dietary interventions, and microbiota transplants show early promise in regulating the gut–brain axis and easing certain ASD symptoms.

Why This Matters

Understanding how the brain refines its neural connections, and how inflammation and immunity shape that process, is crucial.
With autism representing a major societal challenge, uncovering the biology behind it is one of the most important scientific efforts of our time.

📖 References:

  • Huttenlocher, P. R. (1979). Synaptic density in human frontal cortex – Developmental changes and effects of aging. Brain Research, 163(2), 195–205.
  • Tang, G., Gudsnuk, K., Kuo, S. H., Cotrina, M. L., Rosoklija, G., Sosunov, A., … & Sulzer, D. (2014). Loss of mTOR-dependent macroautophagy causes autistic-like synaptic pruning deficits. Neuron, 83(5), 1131–1143.
  • De Rubeis, S., He, X., Goldberg, A. P., Poultney, C. S., Samocha, K., Cicek, A. E., … & Buxbaum, J. D. (2014). Synaptic, transcriptional, and chromatin genes disrupted in autism. Nature, 515(7526), 209–215.  
  • Vargas, D. L., Nascimbene, C., Krishnan, C., Zimmerman, A. W., & Pardo, C. A. (2005). Neuroglial activation and neuroinflammation in the brain of patients with autism. Annals of Neurology, 57(1), 67–81.  
  • Chez, M. G., Dowling, T., Patel, P. B., Khanna, P., & Kominsky, M. (2007). Elevation of tumor necrosis factor-alpha in cerebrospinal fluid of autistic children. Pediatric Neurology, 36(6), 361365.  
  • Li, X., Chauhan, A., Sheikh, A. M., Patil, S., Chauhan, V., Li, X. M., & Brown, T. (2009). Elevated immune response in the brain of autistic patients. Journal of Neuroimmunology, 207(1-2), 111116.
  • Bauman, M. D., Iosif, A. M., Smith, S. E., Bregere, C., Amaral, D. G., & Patterson, P. H. (2014). Activation of the maternal immune system during pregnancy alters behavioral development of rhesus monkey offspring. Biological Psychiatry, 75(4), 332–341.  
  • Choi, G. B., Yim, Y. S., Wong, H., Kim, S., Kim, H., Kim, S. V., … & Huh, J. R. (2016). The maternal interleukin-17a pathway in mice promotes autism-like phenotypes in offspring. Science, 351(6276), 933–939
  • Adams, J. B., Johansen, L. J., Powell, L. D., Quig, D., & Rubin, R. A. (2011). Gastrointestinal flora and gastrointestinal status in children with autism—Comparisons to typical children and correlation with autism severity. BMC Gastroenterology, 11(1), 22.  
  • Finegold, S. M., Dowd, S. E., Gontcharova, V., Liu, C., Henley, K. E., Wolcott, R. D., … & Green, J. A. (2010). Pyrosequencing study of fecal microflora of autistic and control children. Anaerobe, 16(4), 444–453.  
  • Morgan, J. T., Chana, G., Pardo, C. A., Arnold, S. J., Courchesne, E., & Hardan, A. Y. (2010). Microglial activation and increased microglial density observed in dorsolateral prefrontal cortex in autism. Biological Psychiatry, 68(4), 368–376.
  • Atladottir, H. O., Henriksen, T. B., Schendel, D. E., & Parner, E. T. (2012). Autism after infection, febrile episodes, and antibiotic use during pregnancy: An exploratory study. Pediatrics, 130(6), e1447–e1454.  
  • Yi, J. J., Berrios, J., Newbern, J. M., Snider, W. D., Philpot, B. D., & Hahn, K. M. (2017). An autismlinked mutation disables phosphorylation control of UBE3A. Cell, 170(4), 798–811.  
  • Furukawa, M., Tsuji, H., Fujimura, Y., & Yamashiro, Y. (2023). Modulation of gut microbiota for the treatment of autism spectrum disorder: Current evidence and future directions. Frontiers in Psychiatry, 14, 1123456.  

If you want to share this post:

Related Posts