Rewiring of the Serotonin System in Major Depression

Abstract

Serotonin is a key neurotransmitter that is implicated in a wide variety of behavioral and cognitive phenotypes. Originating in the raphe nuclei, 5-HT neurons project widely to innervate many brain regions implicated in the functions. During the development of the brain, as serotonin axons project and innervate brain regions, there is evidence that 5-HT plays key roles in wiring the developing brain, both by modulating 5-HT innervation and by influencing synaptic organization within corticolimbic structures. These actions are mediated by 14 different 5-HT receptors, with region- and cell-specific patterns of expression. More recently, the role of the 5-HT system in synaptic re-organization during adulthood has been suggested. The 5-HT neurons have the unusual capacity to regrow and reinnervate brain regions following insults such as brain injury, chronic stress, or altered development that result in disconnection of the 5-HT system and often cause depression, anxiety, and cognitive impairment. Chronic treatment with antidepressants that amplify 5-HT action, such as selective serotonin reuptake inhibitors (SSRIs), appears to accelerate the rewiring of the 5-HT system by mechanisms that may be critical to the behavioral and cognitive improvements induced in these models. In this review, we survey the possible 5-HT receptor mechanisms that could mediate 5-HT rewiring and assess the evidence that 5-HT-mediated brain rewiring is impacting recovery from mental illness. By amplifying 5-HT-induced rewiring processes using SSRIs and selective 5-HT agonists, more rapid and effective treatments for injury-induced mental illness or cognitive impairment may be achieved.

Tryptophan Metabolism in Depression: A Narrative Review with a Focus on Serotonin and Kynurenine Pathways

“…Indeed, deficits in serotonergic transmission, including reductions in 5-HT neurons and their projections, are associated with this disease and failure of antidepressant responses. Additionally, the most commonly prescribed antidepressants are based on the blockade of 5-HT transporter (5-HTT or SERT), increasing the levels of 5-HT on the synaptic cleft, promoting antidepressant responses [ 6 , 24 ]. MAO enzyme imbalances are also associated with the pathology of depression.…”

5-HT-dependent synaptic plasticity of the prefrontal cortex in postnatal development

“…Serotonin (5-HT) is one of the most influential neuromodulators regulating PFC activity state and synaptic plasticity throughout the entire lifespan, including in the early life ages 17 , 18 . In the mammalian brain, serotonergic neurons are among the first cells to differentiate during postnatal development 19 .…”

“…This property could play a key role in shaping primordial circuits that define cortical functions 6,[13][14][15] . In this respect, it has recently been reported that impairment of excitatory activity during early life leads to reduced dendritic arborization, decreased dendritic spine density, and alterations in circuit formation, which are accompanied by cognitive deficits and maladaptive behaviors 11,16 .Serotonin (5-HT) is one of the most influential neuromodulators regulating PFC activity state and synaptic plasticity throughout the entire lifespan, including in the early life ages 17,18 . In the mammalian brain, serotonergic neurons are among the first cells to differentiate during postnatal development 19 .…”

Sex-specific regulation of binge drinking, social, and arousal behaviors by subcortical serotonin 5HT2creceptor-containing neurons

“…However, whether binge alcohol consumption dysregulates social recognition and arousal behavior in adult rodents has not been explored. The brain's serotonin (5-hydroxytryptamine, 5-HT) system is a critical modulator of affect, motivation, social behavior, arousal, and metabolism (da Cunha-Bang and Knudsen, 2021;Georgescu et al, 2021;Hayes and Greenshaw, 2011;Vahid-Ansari and Albert, 2021). Dysregulation of 5-HT signaling has been implicated in the pathophysiology of numerous psychiatric disorders, including major depression, anxiety disorders, substance use disorders, obsessive-compulsive disorder, and schizophrenia (Nordquist and Oreland, 2010).…”