STAT3 Plays a Key Role in The Behavioural Reactivity of Psychopathology

Date: November 14, 2020 Molecular Psychiatry

Numerous scientific studies show that STAT3 plays an important role in neural function relevant to behaviour in psychiatric disorders. Researchers from MedUni Vienna further clarified that STAT3 controls emotional responses acting as a molecular mediator and plays an key role in the serotonergic system. The findings established a mechanical connection between the immune system, serotonergic transmission and affective disorders (e.g. depression). This work was published in Molecular Psychiatry.

Brief introduction of major depressive disorder (MDD)

Globally, 350 million people suffer from major depressive disorder (MDD), and it is estimated that by 2030, the disease will become the number one cause of disease burden. However, MDD is not the only serious mental illness that has spread with epidemics. There are 60 million people worldwide facing a diagnosis of bipolar depression (BP), and an estimated 21 million people with schizophrenia (SCZ) (available from the following website: http://www.who.com). Despite half a century of in-depth research, our insights into the pathophysiological principles behind these difficult diseases are still incomplete, thus limiting the development of urgently needed new diagnostic and therapeutic strategies.

Signal transducer and activator of transcription 3 (STAT3)

As a member of the STAT family, the transcription factor STAT3 reacts to cytokines and growth factors, and is then phosphorylated by gp130/LIFR-related JAK kinase at tyrosine 705 residue, transfers to the nucleus and activates the transcription of its target genes. It was found that STAT3 is involved in nervous system function, which is very important for controlling behavior under physiological and pathological conditions. Specifically, the focus on STAT3 and its dependent molecular pathways stems from a series of observations: (i) STAT3 is the main coordinator of cytokine activation in the cellular immune process, which is highly related to psychopathology; (ii) In addition to cytokines, the activation of STAT3 can also reflect the effects of many upstream regulators related to neurological function, including growth factors, hormones and endocannabinoids; (iii) STAT3 importantly affects synaptic plasticity events, which may affect the neurological mechanisms related to psychopathology; (iv) Recently, there have been some signs of interrelationships with STAT3 and the serotonergic neurotransmission system. These phenomena are highly related to the etiology of mental illness. However, the interaction between STAT3 signal transduction pathway and neuronal information flow in the brain and its importance in regulating emotional behavior have not been explored.

STAT3 knockout reduces emotional response

Therefore, the research team specifically studied the importance of the STAT3 signal transduction pathway in the serotonin system of the midbrain (emotion regulation center). By specifically inhibiting the STAT3 genetic gene in the mouse model, they found that the behavior of mice lacking serotonergic STAT3 showed reduced negative emotional response and weakened response to amphetamine. In animals lacking STAT3, changes in the firing activity of midbrain neurons were also found. At the level of gene expression, changes in the transcriptional control network of the gene network related to neuropsychiatric diseases were also found. In summary, the research results show that STAT3 plays an important role as a molecular mediator in the serotonergic system that controls emotional responses, thereby establishing a mechanical connection between the immune system, serotonergic transmission and affective disorders.

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Reference

1. Reisinger, S.N., Sideromenos, S., Horvath, O. et al. STAT3 in the dorsal raphe gates behavioural reactivity and regulates gene networks associated with psychopathology. Mol Psychiatry 26, 2886–2899 (2021). Distributed under Open Access License CC BY 4.0.