Isabelle Wilson, Biological Sciences, Spring 2021
Figure 1: Diagram of KYNA-induced blockade of the NMDA receptor which is responsible for symptoms of psychosis. Decreased activation of the GRK3 gene elevates KYNA levels and may provide a pathway to manipulate for future antipsychotic treatments (Source: ResearchGate).
Psychosis currently affects 2-3% of the American population and is characterized by delusions, hallucinations, incoherent speech, and inappropriate behavior. In patients with schizophrenia, psychosis reduces life expectancy by approximately 15 years. Schizophrenia is an incurable chronic brain disorder that causes delusions, hallucinations, disorganized speech, and lack of motivation (Karolinska Institutet, 2021). However, despite the prominent need for antipsychotic treatments, currently available antipsychotics are inefficient and associated with severely detrimental side effects, such as myocarditis (inflammation of the heart muscle) and seizures.
At the Karolinska Institute in Sweden, Carl Sellgren and Sophie Imbeault recently identified a link between psychosis and immune activation of the brain’s glial cells that could be manipulated to create more effective antipsychotic treatments (Karolinska Institutet, 2021). Glia are the non-neuronal cells in the central nervous system (CNS) and peripheral nervous system (PNS) that do not produce electrical impulses but rather maintain homeostasis, form myelin, and provide support for neurons (Jäkel & Dimou, 2017). During CNS injury, microglia can convert into an active phenotype that generate significant innate immune responses and have similar roles as macrophages in the immune response of the CNS (Yang et al., 2010).
Sellgren and Imbeault demonstrated that glia produce kynurenic acid (KYNA), which transmits information from the brain’s immune system to the neurons (Karolinska Institutet, 2021). Therefore, increased sensitivity of the brain’s immune system increases the release of KYNA, which causes an NMDA (N-methyl-D-aspartate) receptor blockade. The NMDA receptor is a glutamate receptor that participates in excitatory neurotransmission and is important for learning new information and forming memories. One hypothesis is that this increased KYNA level is responsible for psychotic symptoms and cognitive defects seen in schizophrenia patients via excessive activation of the NMDA receptor (Kindler et al., 2020).
Additionally, all patients with psychosis have genetic changes in the immune system that cause decreased expression of the protein GRK3 (part of the family of G protein-coupled receptor kinases) (Sellgren et al., 2021). The GRK3 protein normally desensitizes a variety of receptors in the brain, such as dopaminergic and adrenergic receptors, and is linked to reward mechanisms, learning, and memory (Sellgren et al., 2021). Sellgren and Imbeault proved that, compared to controls, mice that lack the GRK3 gene present the psychosis phenotype with elevated levels of KYNA and increased spontaneous firing of midbrain dopamine neurons (Karolinska Institute, 2021). Previous studies have associated excessive dopamine signaling with psychotic symptoms in most individuals with schizophrenia. While the exact underlying neurobiology is still unknown, this conclusion explains the efficacy of antipsychotics as they antagonize dopamine signaling to blunt the expression of symptoms (Kesby et al., 2018). Therefore, this research presents a new pathway to develop novel antipsychotic drugs that may work by increasing GRK3 expression, which would concurrently decrease the sensitivity of the brain’s immune system and minimize NMDA receptor activation.
References
Jäkel, S., & Dimou, L. (2017, January 26). Glial Cells and Their Function in the Adult Brain: A Journey through the History of Their Ablation. Frontiers. https://www.frontiersin.org/articles/10.3389/fncel.2017.00024/full.
Karolinska Institutet. (2021, May 11). New findings linking brain immune system to psychosis. ScienceDaily. Retrieved May 13, 2021 from www.sciencedaily.com/releases/2021/05/210511201118.htm
Kesby, J. P., Eyles, D. W., McGrath, J. J., & Scott, J. G. (2018). Dopamine, psychosis and schizophrenia: the widening gap between basic and clinical neuroscience. Translational psychiatry, 8(1), 30. https://doi.org/10.1038/s41398-017-0071-9
Kindler, J., Lim, C.K., Weickert, C.S. et al. Dysregulation of kynurenine metabolism is related to proinflammatory cytokines, attention, and prefrontal cortex volume in schizophrenia. Mol Psychiatry 25, 2860–2872 (2020). https://doi.org/10.1038/s41380-019-0401-9
Sellgren, C.M., Imbeault, S., Larsson, M.K. et al. GRK3 deficiency elicits brain immune activation and psychosis. Mol Psychiatry (2021). https://doi.org/10.1038/s41380-021-01106-0
Yang, I., Han, S. J., Kaur, G., Crane, C., & Parsa, A. T. (2010). The role of microglia in central nervous system immunity and glioma immunology. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia, 17(1), 6–10. https://doi.org/10.1016/j.jocn.2009.05.006
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