Summary: STAT3 plays a crucial role in the serotonergic system as a molecular mediator for controlling emotional reactivity. The findings establish a link between the immune system, serotonergic transmission, and affective disorders such as depression.
Source: Medical University of Vienna
Numerous scientific studies indicate that inflammatory processes play a key role in the development of psychiatric disorders. One of the areas of particular interest is the interleukin 6/STAT3 signal transduction pathway, which is associated with depression, schizophrenia, and bipolar disorder.
In a study published in leading journal Molecular Psychiatry, MedUni Vienna researchers led by Daniela Pollak from the Division of Neurophysiology and Neuropharmacology showed that STAT3 plays an important role in the serotonergic system as a molecular mediator for controlling emotional reactivity, thereby establishing a mechanistic link between the immune system, serotonergic transmission and affective disorders such as depression.
The STAT3 signal transduction pathway is activated in response to a series of immunogenic and non-immunogenic stimuli, i.e. those that can and those that cannot trigger an immune response.
“It was found that STAT3 is involved in nervous system functions that are important for controlling behaviour in physiological and pathological situations. In an earlier study, we had managed to show that STAT3 also regulates the expression of the serotonin transporter gene,” explains Pollak.
Changes in serotonergic transmission, that is to say the transmission of information from one neuron to another using serotonin as a messenger substance, correlate closely with pathological changes in depression or other affective disorders. However, the interaction between the STAT3 signal transduction pathway and the neuronal information flow in the brain and its importance in regulating emotional behaviour has not yet been explored.
STAT3 deficiency reduces emotional reactivity
The published work therefore specifically investigated the significance of the STAT3 signal transduction pathway in the serotonergic system of the midbrain – an emotional regulation centre – by targeted inhibition of STAT3 in a mouse model.
Says Pollak: “Where STAT3 was selectively absent from the serotonergic system of the midbrain, the mice displayed reduced, negative emotional reactivity in their behaviour and a diminished response to the effects of amphetamine in the brain.
These effects could be detected in mice with reduced STAT3 expression both in a genetic and in a viral model, so that it was possible to rule out developmental changes and to show that an acute manipulation of STAT3 in the adult organism impacts on emotional behaviour.”
In animals lacking in STAT3, there was also found to be a change in the neuronal activity of serotonergic cells of the midbrain. Changes in molecular networks that are significant in neuropsychiatric illnesses were also found on the level of gene expression.
“The results of our study indicate that STAT3 plays an important role as a molecular mediator in the serotonergic system for controlling emotional reactivity, thereby establishing a mechanistic link between the immune system, serotonergic transmission and affective disorders.”
STAT3 in the dorsal raphe gates behavioural reactivity and regulates gene networks associated with psychopathology
The signal transducer and activator of transcription 3 (STAT3) signalling pathway is activated through phosphorylation by Janus kinases in response to a diverse set of immunogenic and non-immunogenic triggers. Several distinct lines of evidence propose an intricate involvement of STAT3 in neural function relevant to behaviour in health and disease. However, in part due to the pleiotropic effects resulting from its DNA binding activity and the consequent regulation of expression of a variety of genes with context-dependent cellular consequences, the precise nature of STAT3 involvement in the neural mechanisms underlying psychopathology remains incompletely understood. Here, we focused on the midbrain serotonergic system, a central hub for the regulation of emotions, to examine the relevance of STAT3 signalling for emotional behaviour in mice by selectively knocking down raphe STAT3 expression using germline genetic (STAT3 KO) and viral-mediated approaches. Mice lacking serotonergic STAT3 presented with reduced negative behavioural reactivity and a blunted response to the sensitising effects of amphetamine, alongside alterations in midbrain neuronal firing activity of serotonergic neurons and transcriptional control of gene networks relevant for neuropsychiatric disorders. Viral knockdown of dorsal raphe (DR) STAT3 phenocopied the behavioural alterations of STAT3 KO mice, excluding a developmentally determined effect and suggesting that disruption of STAT3 signalling in the DR of adult mice is sufficient for the manifestation of behavioural traits relevant to psychopathology. Collectively, these results suggest DR STAT3 as a molecular gate for the control of behavioural reactivity, constituting a mechanistic link between the upstream activators of STAT3, serotonergic neurotransmission and psychopathology.