A light at the end of the tunnel for schizophrenia?

Researchers gain insight into reason for fewer neuronal connections in people with the disease, which could mean a treatable mechanism

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SOLNA, Sweden & BOSTON—A great deal about the etymology, progression and mechanisms of schizophrenia remain unclear, which is the biggest reason effective treatments—much less actual cures—remain elusive. But one thing that has been known, even if the reason behind it was not, is that schizophrenia patients have fewer connections between the neurons in the brain.
In an effort to home in on the reason for that, researchers at Karolinska Institutet in Sweden and Massachusetts General Hospital in the United States were able to create human cell models that confirm there is an excessive degradation of connections in the brain related to schizophrenia. Moreover, they also were able to link this degradation to a genetic risk variant for the disease and demonstrate that the antibiotic minocycline inhibits that degradation.
The study was published in the journal Nature Neuroscience in early February under the title “Increased synapse elimination by microglia in schizophrenia patient-derived models of synaptic pruning.”
As the Karolinska Institutet explained in reporting news of the study results and publication, there exists “a normal extensive pruning of the number of connections between nerve cells, so-called synapses [that] takes place through microglia (the brain’s immune cells) selectively degrading less desirable connections” during the late teenage years. The process, referred to as synaptic pruning, is an important aspect of the development of functional neural networks. Given that many people fall prey to schizophrenia during their late teens, when this process is ongoing, the notion that a connection existed was far from far-fetched.
So, the researchers in the study created induced pluripotent stem cells from schizophrenia patients and reprogrammed them into neurons, thus creating a model of the microglia synaptic pruning in a test tube. Comparisons with matched control subjects indicated a clear increase in the pruning of synapses in schizophrenia patients.
“We also conducted experiments where we combined nerve cells from healthy individuals and diseased microglia, and vice-versa, and could conclude that the excessive pruning in the disease models was due to both a disrupted function of microglia and aberrations in the synapses,” said Jessica Gracias, a doctoral student at the Department of Physiology and Pharmacology at the Karolinska Institutet, and co-author of the study.
Getting to the genetic link indicated earlier, the researchers also studied how different gene variants of the complement factor 4 (C4 gene) affect the pruning. One variant of the complement factor proved to bind more strongly to synapses and result in the increased degradation of synapses. This is consistent with previous genetic findings indicating that this specific C4 risk variant increases the risk of schizophrenia.
“The use of human cells from patients made it possible to study the risk variants directly, because mice lack these specified variants of the C4 gene,” noted Carl Sellgren Majkowitz, research group leader at the Department of Physiology and Pharmacology at the Karolinska Institutet and senior consultant at Region Stockholm, who led the research project together with Roy Perlis at Massachusetts General Hospital.
And finally, we get to clues about possible therapeutics options, as the team “treated” microglia in the cell models with an antibiotic (minocycline), which inhibited the synaptic pruning process.
According to the researchers, they were able to demonstrate a clear protective effect from minocycline treatment in relation to schizophrenia onset by then combing through electronic data records from more than 20,000 individuals who had received either minocycline or another antibiotic during adolescence for treatment of acne.
This research comes almost exactly two years after an unrelated study at the Karolinska Institutet which found, in mouse models, that adjusting levels of a compound called kynurenic acid can have significant effects on schizophrenia-like behavior, a study that was published in the journal Biological Psychiatry.

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