Schizophrenia may be related to vascular changes in the brain

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A study published in Molecular Psychiatry suggests that schizophrenia may be related to changes in the blood vessels in certain areas of the brain. In their work, researchers from Unicamp (Campinas State University), the D’Or Institute for Research and Teaching (Idor) and UFRJ (Federal University of Rio de Janeiro) observed that neurons (astrocytes) derived from patients with the disease stimulate the formation of a greater number of vessels – but thinner ones – which can affect the network of blood vessels in some areas of the brain.

Schizophrenia is a serious, multifactorial mental disorder that can affect up to 1% of the world’s population. Common symptoms include loss of contact with reality (psychosis), hallucinations (hearing voices, for example), false beliefs (delusions), abnormal thinking and behavior, decreased motivation, and deterioration of mental function (cognition).

In the study, the researchers focused attention on the role of astrocytes — cells essential to maintaining neurons and that act as power plants in the central nervous system — in disease progression. In addition to identifying new therapeutic targets, the study has advanced understanding of the molecular mechanisms of the disease.

We have shown that astrocytes may be involved in altering the thickness of cerebral vessels. And this may be related to an important factor in schizophrenia: decreased metabolic flux [produção de energia] in specific areas of the brain. “This reinforces the role of astrocytes as a central component of the disease, making them a target for new therapies,” explains Daniel Martins de Souza, professor at the Institute of Biology at Campinas State University (IB-Unicamp) and one of the authors of the articles.

The work was supported by FAPESP through a thematic project and a postdoctoral grant awarded to Giuliana Minardi Nascimento, first author of the article, along with Pablo Trindade, from UFRJ and Idor.

change in blood vessels

The researchers compared astrocytes derived from skin cells from patients with schizophrenia with those from people without the condition. This part of the study was conducted in the lab of Stevens Rehen, an Idor researcher and professor at the Institute of Biology at UFRJ.

To do this, the team reprogrammed epithelial cells from patients with schizophrenia and those in the control group to regress into the distinct pluripotency stage of stem cells (induced pluripotent stem cells, or iPSCs). It then induced cell differentiation and turned iPSCs into neural stem cells (which can give rise to both neurons and astrocytes).

Previous studies had already suggested that functional and molecular astrocyte abnormalities could be involved in the pathogenesis of schizophrenia. In our work, we confirmed this relationship based on studies with iPS cells. Without this technique, it would be impossible to study astrocytes the way we did,” explains Martins de Souza.

With astrocytes derived from patients and healthy controls, the researchers ran two tests. First, a proteomic analysis (which identifies the set of proteins present in the sample) was performed in Unicamp’s Neuroproteomics Laboratory to investigate the variability of proteins expressed in control cells and those of patients with schizophrenia.

“When we evaluated the proteins of the cells affected with schizophrenia, we noticed the immunological changes associated with the astrocytes. We also found differences in inflammatory cytokines and several other proteins that signal vascular functioning. [que favorece o crescimento de novos vasos] in the cerebral vasculature”, informs Nascimento.

After the proteomic analysis, the researchers performed functional assays. It was observed that the inflammatory response of the astrocytes in the patients was altered and that the substances they released affected the blood vessels. Taking these exams was part of Trinidad’s postdoctoral studies.

For this, the researchers used a model of the vascular system based on the chicken’s amniotic membrane. Known as CAM (English acronym for chicken egg chorionic membrane), the methodology has been used to study the effect of substances on blood vessels in tissues.

This experiment was conducted by collaborators at the University of Chile. “Essentially, we placed the conditioned media of astrocytes, together with all the substances secreted by these cells, within the vascularized region of the fertilized oocyte. As the vascularized cells proliferate, it is possible to check how angiogenesis occurs. Thus, it can be observed whether the substances secreted by the cells The culture medium stimulates or inhibits the formation of blood vessels in the egg, says Trindade.

In addition to modulating angiogenesis, astrocytes derived from patients with schizophrenia showed a chronic inflammation profile. “Astrocytes are known to be neurons that have a role in regulating the immune response in the region. Therefore, it is possible that they promote the increase of immature or less efficient blood vessels. We found that, compared to the control group, astrocytes derived from patients secreted more interleukin.” -8, which is an inflammation signal and is suspected to be the main factor of vascular dysfunction associated with schizophrenia,” the researcher explains to FAPESP.

The authors state that the findings reinforce a role for neurodevelopment in schizophrenia, which, by all indications, is mediated by astrocytes.

Another contribution of the study was to draw attention to the importance of astrocytes in neurological diseases. “The role of glial cells, as in astrocytes, not only in schizophrenia, but in neurological diseases in general, is a recent discovery, as there has been a very neurological insight into investigating the role of neurons. It is still a way to expand our insight and understanding of the disease.” Martinez de Souza assesses.

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