New Evidence for Classic ‘Synaptic Pruning’ Hypothesis of Schizophrenia

In an article published in 1982, noted psychiatrist Irwin Feinberg, M.D., proposed an interesting hypothesis to explain some cases of schizophrenia.

At the time, researchers were well aware that a great deal of reorganization takes place in the brain during adolescence, including the “pruning” or removal of some neuronal connections, or synapses, to make the transmission of signals in the brain more streamlined.

In his piece, Feinberg suggested that improper elimination of synapses during this period—if too many or the wrong connections were pruned—could lead to the profound changes in thoughts and behaviors that underlie the emergence of schizophrenia.

The relationship between defective synaptic pruning and schizophrenia is an elegant theory, but it has been challenging to prove or disprove, noted William Carpenter, M.D., a professor of psychiatry at the University of Maryland School of Medicine and a leading expert on schizophrenia.

“But now we have a cogent story that gives new strength to this old hypothesis,” he told Psychiatric News.

The story Carpenter is referencing is a study that was published January 27 in Nature identifying a gene known as complement component 4 (C4) as a culprit in schizophrenia risk that also appears to be involved with synaptic pruning.

The complement system is a component of the immune system that assists other agents like antibodies and white blood cells in destroying foreign pathogens and clearing out the debris. However, components of the complement system are also known to be involved in synaptic pruning.

C4 specifically had not been previously linked with pruning, but in a comprehensive analysis that combined genomewide analyses, mouse models, and studies of postmortem human brain tissue, a team from the Broad Institute and Harvard Medical School made the connection.

The group, led by Steven McCarroll, Ph.D., director of genetics at the Broad’s Stanley Center for Psychiatric Research, examined human tissue samples and found that C4 protein localizes to the synapses of neurons. Follow-up work in a mouse model that lacked the C4 protein showed that these mice did indeed have lower levels of synaptic pruning as they matured.

The researchers also performed genomic analysis of nearly 65,000 people (28,799 with schizophrenia and 35,986 controls), which suggested that schizophrenia risk was associated with higher expression of the C4A gene. (The C4 protein, like many other parts of the immune system, is composed of multiple genes that are brought together to create the wide structural variability needed to fight infection.)

Additional analysis of human tissue samples (35 schizophrenia and 70 controls) found that schizophrenia patients had about 1.4 times more C4A than the controls.

“This discovery enriches our understanding of the complement system in brain development and in disease, and we could not have made that leap without the genetics,” study coauthor Beth Stevens, Ph.D., a researcher at the Broad Institute and assistant professor of neurology at Harvard Medical School, said in a statement. “We’re far from having a treatment based on this, but it’s exciting to think that one day, we might be able to turn down the pruning process in some individuals and decrease their risk.”

This discovery also helps to potentially resolve an intriguing mystery that surfaced back in 2014 after the Psychiatric Genomics Consortium, led by the National Institute of Mental Health (NIMH), uncovered over 80 new genetic variants associated with schizophrenia risk (Psychiatric News, September 5, 2014).

Along the “genetic skyline” uncovered by the group, a variant located on chromosome 6 produced by far the strongest risk signal. Researchers knew that the variant was located in the major histocompatibility complex (MHC), a region rich with immune system genes, but they were unsure about which MHC gene or genes were driving the risk.

“What makes these findings interesting is that we have now uncovered the potential risk factor from these hundreds of immune genes,” said Vishwajit Nimgaonkar, M.D., Ph.D., a professor of psychiatry and human genetics at the University of Pittsburgh Medical Center, who was not involved in this study. “Yet, the risk mechanism may not be related to immune function, but rather a direct role for C4 in the brain.”

This work was supported by the Stanley Center for Psychiatric Research as well as grants from the National Human Genome Research Institute, National Institute of General Medical Sciences, and NIMH. ■