Summary: New research links psychosis to a genetic change that alters immune signaling in the brain. The study found that reduced expression of GRK3 in people with psychosis related to bipolar disorder is associated with higher levels of the immune-related metabolite kynurenic acid.
Source: Karolinska Institutet
Researchers at Karolinska Institutet in Sweden report evidence connecting psychosis to a genetic alteration that affects the brain’s immune cells.
Published in Molecular Psychiatry, this study may inform the development of new treatments for psychotic symptoms in bipolar disorder and schizophrenia.
Psychosis—experienced by an estimated 2–3% of people—alters perception of reality and often includes hallucinations and paranoia. While most cases are diagnosed as schizophrenia, individuals with bipolar disorder can also develop psychotic symptoms.
Current antipsychotic medications can be insufficient for many patients, leaving substantial unmet clinical needs.
People with schizophrenia have a markedly reduced life expectancy, by roughly 15 years on average compared with the general population, according to Swedish health data.
“Though the precise biological mechanisms behind psychosis remain unclear, accumulating evidence points to immune activation in glial cells as a key contributor. Patients with psychosis show elevated levels of kynurenic acid, a signaling metabolite produced by the brain’s immune system that can influence neuronal function,” says Goran Engberg, Professor at the Department of Physiology and Pharmacology, Karolinska Institutet, and the study’s corresponding author.
Earlier genome-wide association studies (GWAS) linked genetic variation affecting the immune system to altered expression of the protein GRK3 in people with psychosis. The new work delves further into which immune pathways are involved and how they affect brain function.
The research team—including collaborators from the University of California, San Diego and the Mayo Clinic—combined mouse experiments with human genetic data. They studied mice engineered to lack GRK3 in the brain and analyzed genome and cerebrospinal fluid measures from 70 people with bipolar disorder and 48 healthy control subjects.
Their findings indicate that loss of GRK3 increases immune sensitivity in the brain, triggering a cascade that elevates the pro-inflammatory cytokine IL-1β and raises production and turnover of kynurenic acid.
“Our experimental results align with the human genetic analyses: decreased GRK3 expression in people with bipolar disorder who show psychosis corresponds with higher kynurenic acid levels in the brain,” says Carl Sellgren, senior lecturer at the Department of Physiology and Pharmacology, Karolinska Institutet, and the paper’s first author, together with senior researcher Sophie Imbeault.
These data establish a mechanistic connection between immune activation and psychosis, supporting the idea that targeting immune pathways could provide a new direction for antipsychotic drug development.
Most antipsychotic drugs in clinical use were developed in the 1960s, and modern, more effective treatments that act on immune-related mechanisms are needed.
“Developing better, contemporary therapies requires deeper understanding of the brain mechanisms that can trigger psychosis,” says Sophie Erhardt, professor at the Department of Physiology and Pharmacology, Karolinska Institutet, and the study’s senior author.
Funding: The study received support from the Swedish Research Council; the KI–AstraZeneca Translational Science Centre Joint Research Program; the Torsten Söderberg Foundation; the Foundation for Strategic Research; the Brain Foundation; the Petrus and Augusta Hedlund Foundation; the Marta Lundqvist Foundation; the Åhlen Foundation; the US National Institute of Mental Health; the Stanley Medical Research Institute; Region Stockholm–Karolinska Institutet’s ALF agreement; the Broad Institute; the Knut and Alice Wallenberg Foundation; and a Mayo Clinic–Karolinska Institutet collaborative grant.
Conflicts of interest: Carl Sellgren serves as a scientific advisor to Outermost Inc., USA. Doo-Sup Choi is a board member of Peptron Inc., USA. Maria Bhat is employed by AstraZeneca. No other conflicts were reported.
About this psychosis research news
Source: Karolinska Institutet
Contact: Press Office, Karolinska Institutet
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Original Research: Open access. “GRK3 deficiency elicits brain immune activation and psychosis” by Carl M. Sellgren et al., published in Molecular Psychiatry.
Abstract
GRK3 deficiency elicits brain immune activation and psychosis
GRK3, a member of the G protein-coupled receptor kinase family, has been implicated in the biology of schizophrenia and bipolar disorder. Post-mortem studies have shown reduced GRK3 expression and protein levels in the prefrontal cortex of schizophrenia patients.
This study evaluates behavior and neurotransmission linked to immune activation and psychosis using mice lacking functional Grk3. The approach combined behavioral testing with biochemical, electrophysiological, molecular, and imaging techniques.
Compared with wild-type controls, Grk3−/− mice display several alterations associated with psychosis: increased brain IL-1β, elevated kynurenic acid turnover, heightened sensitivity to d-amphetamine, increased spontaneous firing of midbrain dopamine neurons, and impaired prepulse inhibition. Human genetic analyses further connect psychotic features in bipolar disorder with reduced GRK3 expression and higher cerebrospinal fluid kynurenic acid.
Together, these results indicate that Grk3−/− mice model key aspects of the psychosis phenotype, including glial activation, and represent a relevant platform for translational studies of novel immunomodulatory treatments for psychotic disorders.