Schizophrenia

CAN SCHIZOPHRENIA BE PREVENTED?

Researchers believe that schizophrenia occurs when a type of cells in the brain, called microglia, are overactive. These then cut connections between nerve cells – including those that would normally be retained. Carl Sellgren Majkowitz is now to study in detail whether this can be prevented – and if so, how.

“Another aim is to find markers that make it possible to identify those at increased risk of developing schizophrenia.”

On average, one in a hundred people suffer from schizophrenia, which is a chronic psychiatric illness. Carl Sellgren Majkowitz is a researcher at Karolinska Institutet and a Senior Consultant in Psychiatry; his interest in research in this area grew out of meeting such patients over the past 15 years.

“In my research I want to carry out relevant experiments in the lab to map the biological processes behind the illness, so that we can use this to improve clinical treatment,” he says.

The objective of the project he is leading is to investigate why schizophrenia arises and whether it is possible to prevent it from occurring. The development of knowledge about schizophrenia at cellular level could be described as a multistage rocket.

As early as 1982 the question was raised whether a lack of connections between nerve cells in the brain was behind the illness. Post mortem results indicated that individuals with schizophrenia had fewer connections between the nerve cells in the front part of the brain than individuals without schizophrenia.

It then took until 2012 until researchers were able to show in tests on mice that there are specific cells in the brain, microglia, that are responsible for eliminating connections between nerve cells.

And in 2019 Carl Sellgren Majkowitz made an important discovery:

“Using two-dimensional cell cultures with microglia cells and nerve cells derived from patients’ skin cells, we were able to show that microglia cells from individuals with schizophrenia were more active in eliminating connections between nerve cells,” says Carl Sellgren Majkowitz.

As the brain matures, its nerve cells link up. These connections are called synapses. It is via the synapses that the nerve cells send signals to each other. In the late teenage years, however, it is time for the microglia cells to eliminate the connections that are not being used in order to reinforce the more important networks.

In the study, which was published in the journal Nature Neuroscience, the researchers also made another discovery – the result of an idea that Carl Sellgren Majkowitz describes as a ‘shot from the hip’.

“In another context an antibiotic called minocycline had an inhibiting effect on these very microglia cells. We asked ourselves whether this effect might affect the risk of getting schizophrenia,” he says.

They collected data from the health records of 20,000 young people who had been prescribed minocycline to treat acne in their teenage years. Those who had later been diagnosed with schizophrenia were then followed up.

“We saw that the incidence of schizophrenia was significantly lower among those treated with minocycline when compared with others,” he says.

The project The rewiring of the connectome in adolescence as a target for preventing schizophrenia is now on the starting blocks. In this project the

researchers want to create three-dimensional cell cultures – a kind of highly simplified “mini-brains” that better reflect how the brain is than the twodimensional cultures used previously.

“We are using the Nobel Prize-winning method that involves getting mature cells to return to being stem cells,” says Carl Sellgren Majkowitz.

Skin cells are used as the starting material. When they are converted back into stem cells, these can in turn form the desired cell type – in this case, nerve cells and microglia cells.

As a further refinement, the skin cells were taken from five pairs of identical twins where one sibling had been affected by schizophrenia but not the other.

“That means that in the cultured cells we can compare how the microglia cells behave. We want to understand the process in which they eliminate connections, so we will be analysing all the active genes and the proteins formed in the cells,” he says. This could give an indication of which genes are behind the excessive elimination.

“We also want to find ways to prevent this, for example by testing minocycline on the cell cultures. Another aim is to find markers that make it possible to identify those at increased risk of developing schizophrenia,” says Carl Sellgren Majkowitz.

The work has already started but the results are likely to take a couple of years to emerge, says Carl Sellgren Majkowitz, who highlights the importance of the support from the Erling-Persson Foundation.

“It’s a hugely important award that enables us to plan for the longer term. Our methods are demanding and we need to be able to employ international researchers with the expert knowledge required and ensure that they can stay in Sweden for a lengthy period,” he says.

35,000

Schizophrenia affects around one in a hundred people. In Sweden 35,000 people are estimated to be living with schizophrenia.

13–19

The onset of the illness occurs during the late teenage years, often accompanied by psychosis. Common symptoms include delusions, hallucinations and thought disorders.

Today’s medicines often reduce the psychotic symptoms, but have no clear effect on symptoms such as cognitive impairment and lack of motivation.

ABOUT THE PROJECT Project Manager: Carl Sellgren Majkowitz leads the research group at the Department of Physiology and Pharmacology at Karolinska Institutet and is Senior Consultant in Psychiatry for the North-west Region of Stockholm.

Title: ‘The rewiring of the connectome in adolescence as a target for preventing schizophrenia’.

What it involves: Using cultured three-dimensional “mini-brains”, researchers want to study how the volume of connections between nerve cells – known as synapses – are modified. This normally takes place during adolescence, and now they want to study – among other things – whether the degree of pruning can be inhibited by medical drugs.

Funding: The Erling-Persson Foundation is supporting the project with SEK 3 million per year for five years, totalling SEK 15 million. The project is being funded within the framework of the Swedish Foundations’ Starting Grant, set up by a group of foundations. startinggrant.se

Read more: Journal of Psychiatric Research 1982-83: https://pubmed.ncbi.nlm.nih.gov/7187776/ Neuron 2012: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3528177/

Sellgren’s study: Nature Neuroscience 2019: https://www.nature.com/articles/s41593-018-0334-7