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

Abstract

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."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.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/

Microglial Pruning: Relevance for Synaptic Dysfunction in Multiple Sclerosis and Related Experimental Models

“…In addition to situations where dysregulated pruning likely occurs at developmental stages, many recent data point to a reactivation of the pruning machinery in adults as a consequence of the decrease in synaptic activity that occurs during ageing or as a result of neuronal damage [ 48 ]. The loss of presynaptic terminals and dendritic spines, together with the activation of glial cells, are early pathogenic mechanisms that strongly correlate with CD in a number of neurodegenerative diseases.…”

Analyses of GWAS and sub-threshold loci lead to the discovery of dendrite development and morphology dysfunction underlying schizophrenia genetic risk

“…Synaptic loss and dendritic atrophy have been reported for neurodevelopmental and neurodegenerative disorders like SCZ, MDD and Alzheimer disease (AD) (Lin and Koleske, 2010), suggesting a possible therapeutic strategy of maintaining normal dendritic architecture and restoring its related functions (e.g., synapse development). Perhaps preventing synaptic over-pruning during childhood and adolescence could be bene cial (Sakai, 2020). Supporting evidence from an earlier study showed that people chronically exposed to minocycline, an antibiotic with anti-in ammatory effects that reduces pruning, are at signi cant lower risk of incident psychosis (Sellgren et al, 2019).…”

The Safeguarding Microglia: Central Role for P2Y12 Receptors

“…In the healthy brain microglial processes are constantly contacting synaptic contacts located on neuronal dendrites. These microglia-dendritic contacts are instrumental for synaptic pruning in early development, which removes silent, aberrant or redundant synapses by en passant phagocytosis ( Sierra et al, 2010 ) thus contributing to shaping neuronal ensembles and supporting neuroplasticity ( Kettenmann et al, 2013 ; Sakai, 2020 ). Synaptic pruning is controlled by neuronal complement system ( Stevens et al, 2007 ; Schafer et al, 2012 ), which tags the synapses to be removed, and by neurone-derived chemokine CX3CL1 also known as fractalkine.…”