How synaptic pruning works
Neurodevelopmental disorders
Latest research and technologies
Implications for treatment
Conclusion
Synaptic pruning is a crucial neurodevelopmental process through which the brain refines its neural circuitry by systematically eliminating excess or weak synaptic connections. During early childhood and adolescence, the brain creates an abundance of synapses, forming potential communication pathways between neurons.
However, not all these connections prove equally necessary or efficient. Pruning selectively removes those that are seldom used, thereby enhancing the overall efficiency of neuronal signaling. This streamlined structure leads to more precise information transfer and fosters cognitive skills, such as learning and memory.
By retaining only the most active and beneficial connections, pruning contributes to the brain’s ability to adapt to environmental demands and experiences. Although synaptic pruning is most intense during childhood and adolescence, it continues, at a reduced pace, throughout adulthood.
Ultimately, this process underpins healthy brain development, ensuring that neural networks evolve into sophisticated, specialized systems capable of complex functions and lifelong plasticity.1
This article explains synaptic pruning, its role in brain development, and its implications for neurological and psychiatric conditions.
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How synaptic pruning works
At birth, the brain has an abundance of synapses, far more than it will retain in adulthood. As a child learns and interacts with the environment, active synapses are strengthened while weaker, unused ones are gradually removed. This process is essential for efficient information processing and cognitive development.2
The mechanisms of synaptic pruning rely on activity-dependent selection, microglial involvement, and molecular signaling. Neural activity determines which synapses are preserved; those frequently used become stronger, while inactive ones weaken and are marked for removal.
Microglia, the brain’s immune cells, play a crucial role by engulfing these weak synapses. Specific molecules, such as complement proteins (C1q, C3, and C4) and fractalkine signaling, help identify and tag synapses for elimination, guiding microglia in their role.2
This pruning process unfolds in key phases. During infancy and early childhood (0-5 years), synaptic density peaks, allowing for rapid learning and sensory development. From childhood through adolescence, pruning intensifies, particularly in the prefrontal cortex, which governs reasoning and decision-making. By adulthood, the process stabilizes, ensuring a refined neural network.2
Disruptions in synaptic pruning have been linked to neurodevelopmental disorders. Excessive pruning is associated with schizophrenia, leading to reduced synaptic connectivity, while insufficient pruning may contribute to autism, resulting in excessive neural connections.
Understanding the precise mechanisms of pruning offers potential avenues for therapeutic interventions in these conditions.2
Neurodevelopmental disorders
Emerging research highlights shared neurobiological pathways between Autism Spectrum Disorders (ASD) and Childhood-Onset Schizophrenia (COS). Both conditions exhibit developmental brain abnormalities, particularly in synaptic pruning, a process crucial for refining neural connections.
In ASD, excessive early brain growth suggests reduced pruning, leading to hyperconnectivity and deficits in social and cognitive processing. Conversely, COS is associated with excessive synaptic pruning, resulting in progressive gray matter loss and cognitive decline.2,3
Genetic studies reveal overlapping risk factors, including copy number variations (CNVs) in regions like chromosome 22, long arm, band 11.2 (22q11.2) and chromosome 16, short arm, band 11.2 (16p11.2), implicating synaptic function genes such as Neurexin 1 (NRXN1).
Family studies indicate a higher prevalence of schizophrenia-like traits among relatives of autistic individuals, reinforcing a shared genetic susceptibility. Brain imaging findings also suggest a developmental trajectory shift; ASD shows early overgrowth, while COS follows exaggerated cortical thinning.3
Clinically, COS often coexists with ASD symptoms, with 30-50% of COS cases having prior pervasive developmental disorder diagnoses. This blurs traditional diagnostic boundaries and suggests a continuum of neurodevelopmental impairment rather than distinct disorders. Future research focusing on early intervention and genetic markers may refine diagnostic criteria and treatment approaches for these overlapping conditions.3
Synaptic Pruning, Animation
Latest research and technologies
Advanced imaging techniques and genetic studies have significantly enhanced our understanding of this process and its implications for neurodevelopmental and neurodegenerative disorders.
Recent imaging studies have provided real-time visualization of synaptic pruning, revealing how neural activity determines which synapses are retained or eliminated.
High-resolution microscopy and live imaging have allowed researchers to observe microglial interactions with synapses, showing that immune cells actively participate in pruning. Disruptions in this process have been linked to conditions like schizophrenia and autism, where either excessive or insufficient pruning affects brain connectivity.3,4
Genetic research has identified key molecular players in synaptic pruning. Studies on complement proteins, such as C4, suggest that genetic variations influencing its expression may contribute to neurodevelopmental disorders.
Genome-wide association studies have linked increased C4 activity to excessive pruning in schizophrenia, while insufficient pruning has been observed in autism. Additionally, genes regulating microglial activity and immune signaling pathways have been implicated in synapse elimination and neurological disorders.4
By combining imaging and genetic insights, researchers are uncovering potential therapeutic targets for conditions where synaptic pruning is dysregulated. These advances could lead to early interventions for neurological disorders and improve our understanding of brain plasticity.4
Uncovering the Mystery of the Human Brain with Computational Neuroscience
Implications for treatment
While essential for normal neural circuit refinement, excessive pruning is implicated in neurodegenerative disorders such as Alzheimer’s disease, Huntington’s disease, multiple sclerosis, and radiation-induced cognitive decline.5
Therapeutic strategies focus on modulating complement proteins like C1q, C3, and C5a, which drive synapse elimination under pathological conditions. Genetic or pharmacological inhibition of these components has shown promise in preclinical models.
For example, blocking C1q or C3 preserves synapses and prevents cognitive impairment in Alzheimer’s disease and multiple sclerosis models. Additionally, Complement Component 5a receptor 1 (C5aR1) antagonists such as PMX205 have demonstrated neuroprotection by reducing inflammation and synaptic loss.5
Beyond complement inhibition, microglial modulation is another promising avenue. Targeting receptors like CR3, Triggering Receptor Expressed on Myeloid Cells 2 (TREM2), or Signal Regulatory Protein Alpha (SIRPα) can regulate synaptic engulfment, minimizing excessive pruning while preserving physiological function. Astrocyte-targeted therapies involving Apolipoprotein E (APOE) and Multiple Epidermal Growth Factor 10 (Megf10)/Mer Tyrosine Kinase (MERTK) pathways are also under exploration.5
Given synaptic pruning's dual role in development and disease, precise, stage-specific interventions are crucial. Advances in gene therapy, small-molecule inhibitors, and biologics offer the potential for tailored treatments that minimize neurodegeneration while preserving cognitive function.
Neurodevelopment: From Embryo to Adult Brain
Conclusion
Neuroscience research continues to unveil the intricate mechanisms underlying synaptic pruning, a process essential for brain development and plasticity. Key insights highlight that synaptic refinement is governed by activity-dependent selection, microglial involvement, and molecular signaling.
Disruptions in this process have profound implications for neurodevelopmental and neurodegenerative disorders, with excessive pruning linked to schizophrenia and neurodegeneration, while insufficient pruning contributes to autism and hyperconnectivity disorders.
Technological advancements, particularly in high-resolution imaging and genetic studies, have enabled real-time observation of microglial-synapse interactions and identified molecular regulators like complement proteins and immune signaling pathways. These breakthroughs provide new perspectives on how synaptic connectivity is shaped during development and altered in disease states.
Future directions in neuroscience will focus on translating these insights into targeted interventions. Therapeutic strategies aim to modulate complement pathways, microglial activity, and astrocyte functions to restore synaptic balance in neurodevelopmental and neurodegenerative disorders.
Gene therapy, biologics, and small-molecule inhibitors hold promise for precise, stage-specific treatments that minimize pathological synapse loss while preserving cognitive function. As research progresses, integrating imaging, genetics, and computational modeling will refine our understanding of brain plasticity, paving the way for early diagnosis and personalized treatment strategies.
By bridging fundamental neuroscience with clinical applications, future studies will continue to unravel the complexities of brain function, offering new hope for therapeutic advancements in neurological and psychiatric disorders.
References
- Petrisko, T. J., Gomez-Arboledas, A., & Tenner, A. J. (2021). Complement as a powerful “influencer” in the brain during development, adulthood and neurological disorders. Advances in immunology, 152, 157-222.
- Sakai, J. (2020). How synaptic pruning shapes neural wiring during development and, possibly, in disease. Proceedings of the National Academy of Sciences, 117(28), 16096-16099.
- Rapoport, J., Chavez, A., Greenstein, D., Addington, A., & Gogtay, N. (2009). Autism spectrum disorders and childhood-onset schizophrenia: clinical and biological contributions to a relation revisited. Journal of the American Academy of Child & Adolescent Psychiatry, 48(1), 10-18.
- Hindley, N., Sanchez Avila, A., & Henstridge, C. (2023). Bringing synapses into focus: Recent advances in synaptic imaging and mass-spectrometry for studying synaptopathy. Frontiers in Synaptic Neuroscience, 15, 1130198.
- Gomez-Arboledas, A., Acharya, M. M., & Tenner, A. J. (2021). The role of complement in synaptic pruning and neurodegeneration. ImmunoTargets and Therapy, 373-386.
Further Reading