Too Many Connections: How Impaired Synaptic Pruning Shapes the Autistic Brain

The human brain is often described as the most complex structure in the known universe. From the final trimester of pregnancy through early childhood, the brain undergoes synaptogenesis — the creation of trillions of molecular bridges connecting neurons for communication. These synapses form rapidly, creating a dense web of connectivity. But, to function effectively, the brain must later refine and optimize these connections through synaptic pruning, a process that eliminates weaker or unnecessary synapses to streamline neural networks.

Synaptic pruning is not a pathology: it’s a feature observed in all organisms. By selectively removing certain connections, the brain ensures that the most efficient, meaningful pathways remain. This helps fine-tune everything from movement, to memory, emotion, and social behavior. Pruning is most active during childhood and adolescence, aligning with periods of intense learning and developmental change. It’s guided by both genes and experience: synapses that are used frequently get stronger and survive, while those that remain quiet are tagged for removal.

In autism spectrum disorder (ASD), researchers have uncovered evidence that the pruning process is disrupted. Instead of sculpting a refined, efficient network, the brain remains in a hyperconnected state - and, while that might sound beneficial, the reality is more complicated. Too many synapses can cause sensory overload, slowing down information processing, and difficulties filtering relevant from irrelevant stimuli — all hallmarks of autism.To understand why this matters, it helps to explore what drives synaptic pruning at the molecular level. 

"[Synaptic pruning] helps fine-tune everything from movement, to memory, emotion, and social behaviour."

A synapse is a bridge between a (pre-synaptic) neuron's axon terminal and a (post-synaptic) neuron's dendrites. The pre-synaptic neuron releases neurotransmitters (dopamine, glutamate, noradrenaline, acetylcholine) that are received by receptors (molecular gates opening on neurotransmitter binding to allow for subsequent signalling) present on membranes of post-synaptic neuron membranes. Together, this process allows for communication between neurons. 

Scaffold proteins like Piccolo and Bassoon help organize the presynaptic side of neurons, while PSD95, SHANK, GKAP, and Homer shape the structure of dendritic spines on the postsynaptic side. Proteins such as Liprin-α, ELKS/CAST, and RIM set up active zones where neurotransmitters are released. Neurexin and neuroligin act as adhesion molecules, holding neurons together at synapses. Released neurotransmitters bind to receptors like AMPA, NMDA, GABA, and nAChR, passing the signal to the next neuron. AMPA and NMDA receptors also let calcium into the cell, triggering kinases like PKC and CaMKII. Frequently used synapses get stronger thanks to molecules like BDNF and LRRTM, which help mature and stabilize them. In contrast, less active synapses are broken down by microglia.

Microglia, or the brain’s immune cells, act like the brain’s garbage collectors, identifying and removing unnecessary synapses. But, they don’t work alone: they rely on signaling molecules like complement proteins (notably C1q and C3), which tag synapses with a 'delete me' signal for removal. Additionally, inactive or redundant synapses also expose ‘eat me’ signals, such as phosphatidylserine (PS) on their membranes, which make them visible to microglia. Microglia then recognize these tags using receptors like CR3 and proceed to engulf the synapse via phagocytosis.

"In ASD, mutations in genes tied to synaptic pruning (...) can interfere with the tagging and removal process."

In a healthy brain, this system runs smoothly. Active (mature) synapses are spared from pruning because their use reinforces protective signals. Proteins like CD47 act as “don’t eat me” markers, shielding essential synapses. Together, this dynamic balance ensures that only the right connections are pruned, shaping a functional and focused neural network.

In ASD, several things can go wrong. First, mutations in genes tied to synaptic pruning — such as FMR1, SHANK, PCDH10, and Sez6 — can interfere with the tagging and removal process. Some of these genes regulate the transcription of proteins that determine which synapses should be eliminated, while others affect the structure or stability of synapses themselves. When disrupted, the pruning machinery either fails to mark synapses for removal or removes them inefficiently.

Second, the complement system may be dysregulated. If C1q or C3 proteins are underexpressed or malfunctioning, microglia may not prune the correct signals. Conversely, if regulatory proteins like Sez6 are missing, too many synapses might be marked, overwhelming the system. Either way, pruning becomes imprecise and incomplete.

Third, the microglia themselves may be less responsive. Studies show that in some cases of autism, microglial cells do not respond adequately to “eat me” signals, meaning they ignore synapses that should be cleared away. This could result from inflammation, disrupted calcium signaling, or defective receptor function.

"When excess synapses clutter the landscape, the brain has a harder time coordinating responses, recognising patterns, or adapting to change."

One of the most important regulators of synaptic pruning is the mTOR pathway, a signaling cascade that controls cellular growth and metabolism. In the brain, mTOR activity influences autophagy — the cell’s recycling process that includes synapse removal. Overactivation of the mTOR pathway, which has been observed in several autism models, suppresses autophagy and reduces synaptic pruning. This results in an excess of synaptic connections, particularly in sensory and prefrontal cortical regions.

With too many synapses, neural networks become noisy and inefficient. Brain regions may be hyperconnected, but not in a way that improves function. For example, individuals with autism often experience sensory hypersensitivity — lights may seem too bright, sounds too loud, textures overwhelming. Social communication also suffers. The prefrontal cortex, which governs social behavior, decision-making, and flexible thinking, relies on clean, efficient signaling. When excess synapses clutter the landscape, the brain has a harder time coordinating responses, recognizing patterns, or adapting to change. This helps explain the repetitive behaviors, narrowed interests, and difficulties with social interaction commonly seen in autism.

"In some cases of autism, microglial cells do not respond adequately to “eat me” signals, ignoring synapses that should be cleared away."

Importantly, this isn’t just theoretical. In mouse models of autism, reducing mTOR activity with specific drugs can normalize synapse numbers and improve behavior. This suggests that even late in development, the brain retains some plasticity (ie. capacity to remodel itself) when the underlying biology is corrected. While we’re far from clinical treatments that safely and effectively adjust pruning in humans, these findings are a powerful proof of concept.

Synaptic pruning is not a minor detail in brain development, but one of the most fundamental processes. It requires coordination between genes, immune signals, neural activity, and cellular pathways. When that coordination breaks down, as it does in many forms of autism, the result is a brain that forms connections but struggles to refine them. Understanding the molecular and cellular mechanisms behind the pruning imbalance gives us a clearer picture of autism as a complex developmental difference, rooted in how the brain builds and edits itself. With deeper knowledge, we move closer to interventions that may one day help restore balance — not by changing who someone is, but by supporting how their brain works best.

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This article was written by Shriya Singh and edited by Julia Dabrowska, with graphics produced by Georgina Savastano. If you enjoyed this article, be the first to be notified about new posts by signing up to become a WiNUK member (top right of this page)! Interested in writing for WiNUK yourself? Contact us through the blog page and the editors will be in touch.