Core Concept: How synaptic pruning shapes neural wiring during development and, possibly, in disease

Jill Sakai

PNAS July 14, 2020 117 (28) 16096-16099

At birth, an infant’s brain is packed with roughly 100 billion neurons—some 15% more than it will have as an adult. As we learn and grow, our experiences strengthen the circuits that prove most relevant while the others weaken and fade.

Figure: Nerve cells in the cerebellum called purkinje cells (blue) are among the brain cells that undergo synaptic pruning as we age. Researchers are starting to recognize how pruning gone awry in children and teenagers could lay the foundation for neurological disorders. Image credit: Science Source/NIGMS/Yinghua Ma/Timothy Vartanian/Cornell University.

“One extreme view of this would be that you start out wired up for every possible contingency,” says Jeff Lichtman, a neuroscientist at Harvard University in Cambridge, MA. Over time, a large percentage of those wires are permanently disconnected, says Lichtman. “What you're left with is a narrower nervous system,” he explains. “But it’s tuned exactly to the world you found yourself in.”

The process of elimination is key to forming a healthy, adaptive brain. Researchers have documented waves of neuronal cell death and the dramatic reduction of neurons’ connecting axon fibers early in neural development. But synapses, the fixed points where one cell’s axon exchanges signals with another cell, continue to be selectively removed at least through adolescence in humans, refining a coarse neural map into mature circuits.

With improved imaging techniques and molecular tools, researchers are now exploring why synaptic pruning—the targeted elimination of functional synapses—happens and how it works. The amount and timing of neural activity are central to determining which synapses get reinforced and retained, and which get weaker—which flags them for destruction. Elements of the immune system appear to be essential to carrying out the elimination process. But researchers are also coming to recognize how pruning gone awry in children and teenagers could lay the foundation for neurological disorders, such as schizophrenia or autism. One possibility is that these are diseases of the wiring diagram—what Lichtman terms “connectopathies.” It may also be the case that some of the same pruning mechanisms that normally help refine brain wiring early in life contribute to later pathological synapse loss in dementia and other neurodegenerative disorders. If so, the pruning machinery could be a therapeutic target.

See more https://www.pnas.org/content/117/28/1609