Brain Immune System Linked to Psychosis

Summary: A link has been identified between psychosis and a genetic change that alters the immune system in the brain. Researchers found people with psychosis associated with bipolar disorder had decreased expression of GRK3. This led to an increased amount of kynurenic acid in the brain.

Source: Karolinska Institute

New research at Karolinska Institutet in Sweden suggests a link between psychosis and a genetic change that affects the brain’s immune system.

The study published in Molecular Psychiatry may impact the development of modern medicines for bipolar disorder or schizophrenia.

Psychosis affects approximately 2-3 per cent of the population and is characterized by a change in the perception of reality, often with elements of hallucinations and paranoid reactions.

Most of the people affected are patients with schizophrenia, but people with bipolar disorder may also experience psychotic symptoms.

The antipsychotics available today often have insufficient efficacy, and for patients, their life situation can be difficult.

The average life expectancy of people with schizophrenia is approximately 15 years shorter than that of the general population, according to Sweden’s National Board of Health and Welfare.

“It is not entirely known what biological mechanisms cause psychosis, but recent research suggests that immune activation in the brain’s glial cells may be the cause. People with psychosis have elevated levels of kynurenic acid in the brain, a messenger that transmits information from the brain’s immune system to the neurons,” says Goran Engberg, Professor at the Department of Physiology and Pharmacology, Karolinska Institutet, and the study’s corresponding author.

Previous genome-wide association studies (GWAS) have shown that the protein GRK3 expresses itself via genetic changes in the immune system in patients with psychosis.

Now researchers at Karolinska Institutet, the University of California, San Diego, USA, and the Mayo Clinic, Rochester, USA, have studied more specifically which parts of the immune system impact psychotic disorders.

The study is based on extensive data from mice that lack the GRK3 protein in the brain, as well as an analysis of the genome from 70 people with bipolar disorder and 48 healthy control subjects.

Results show that the loss of the GRK3 protein appears to increase the sensitivity of the immune system and triggers a cascade of effects in the brain, involving an increased release of the cytokine IL-1beta and kynurenic acid.

This shows the outline of a head
The antipsychotics available today often have insufficient efficacy, and for patients, their life situation can be difficult. Image is in the public domain

“Our experimental data are confirmed through genetic studies where we see a link between psychosis in patients with bipolar disorder and decreased expression of GRK3, which leads to an increased amount of kynurenic acid in the brain,” says Carl Sellgren. He is a senior lecturer at the Department of Physiology and Pharmacology, Karolinska Institutet, and the study’s first author together with Sophie Imbeault, senior researcher at the same department.

The data in the study provide a connection between immune activation and psychosis and thus presents a starting point for further study of novel antipsychotic drugs possessing immune modulatory functions.

The drugs currently used in psychosis treatment were developed in the 1960s.

“To develop effective, modern drugs, more knowledge is needed about the mechanisms in the brain that can trigger psychosis,” says Sophie Erhardt, professor at the Department of Physiology and Pharmacology, Karolinska Institutet, and the study’s last author.

Funding: The study was funded by the Swedish Research Council, The KI-AstraZeneca Translational Science Centre Joint Research Program, the Torsten Soderberg Foundation, the Foundation for Strategic Research and the Brain Foundation, Petrus and Augusta Hedlund Foundation, Marta Lundqvist Foundation, Ahlen Foundation, National Institute of Mental Health, the Stanley Medical Research Institute, Region Stockholm-Karolinska Institutet’s ALF Agreement for Clinical Research and Medical Education, the Broad Institute, the Knut and Alice Wallenberg Foundation, the Mayo Clinic – Karolinska Institutet Collaborative Project Grant.

Carl Sellgren is a scientific advisor to Outermost Inc, USA. Doo-Sup Choi sits on the board of Peptron Inc, USA, and Maria Bhat is employed by AstraZeneca. There are no other reported conflicts of interest.

About this psychosis research news

Source: Karolinska Institute
Contact: Press Office – Karolinska Institute
Image: The image is in the public domain

Original Research: Open access.
GRK3 deficiency elicits brain immune activation and psychosis” by Carl M. Sellgren, Sophie Imbeault, Markus K. Larsson, Alfredo Oliveros, Ida A.K. Nilsson, Simone Codeluppi, Funda Orhan, Maria Bhat, Maximillian Tufvesson-Alm, Jessica Gracias, Magdalena E. Kegel, Yiran Zheng, Anthi Faka, Marie Svedberg, Susan B. Powell, Sorana Caldwell, Mary E. Kamenski, Marquis P. Vawter, Anton Schullman, Michel Goiny, Camilla I. Svensson, Tomas Hokfelt, Martin Schalling, Lilly Schwieler, Simon Cervenka, Doo-Sup Choi, Mikael Landen, Goran Engberg, Sophie Erhardt. Molecular Psychiatry


Abstract

GRK3 deficiency elicits brain immune activation and psychosis

The G protein-coupled receptor kinase (GRK) family member protein GRK3 has been linked to the pathophysiology of schizophrenia and bipolar disorder. Expression, as well as protein levels, of GRK3 are reduced in post-mortem prefrontal cortex of schizophrenia subjects.

Here, we investigate functional behavior and neurotransmission related to immune activation and psychosis using mice lacking functional Grk3 and utilizing a variety of methods, including behavioral, biochemical, electrophysiological, molecular, and imaging methods.

Compared to wildtype controls, the Grk3−/− mice show a number of aberrations linked to psychosis, including elevated brain levels of IL-1β, increased turnover of kynurenic acid (KYNA), hyper-responsiveness to D-amphetamine, elevated spontaneous firing of midbrain dopamine neurons, and disruption in prepulse inhibition. Analyzing human genetic data, we observe a link between psychotic features in bipolar disorder, decreased GRK expression, and increased concentration of CSF KYNA.

Taken together, our data suggest that Grk3−/− mice show face and construct validity relating to the psychosis phenotype with glial activation and would be suitable for translational studies of novel immunomodulatory agents in psychotic disorders.

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