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.
Highlights
Major Depressive Disorder (MDD) is characterized by a persistent low mood as a core symptom
These results suggest that growthassociated protein 43 (GAP-43) and stable tubule only polypeptide (STOP) proteins are the key regulators of normal 5-HT outgrowth and innervation in healthy conditions
Not extensively studied, increasing evidence is indicating that deficiencies in 5-HT innervation associated with development, chronic stress or brain injury may lead to depression [10]
Summary
Major Depressive Disorder (MDD) is characterized by a persistent low mood as a core symptom. Using a semi-automated approach that combines immunohistochemistry and high-resolution confocal microscopy to label 5-HTT immunoreactive axons has allowed researchers to reconstruct the 5-HT axons in 3D through their distribution within limbic brain regions [114, 115] Using this approach, the changes in 5-HT axon properties have been determined in a model of post-stroke depression induced by focal ischemia in mice medial prefrontal cortex (mPFC), before and after treatment with chronic fluoxetine [64]. Chronic fluoxetine treatment induced a full recovery from monocular deprivation in adult rats by increasing brain-derived neurotrophic factor (BDNF) expression to reduce GABAergic activity in the visual cortex enhancing excitatory long-term potentiation [188] These actions of fluoxetine suggest that synaptic, possibly structural re-organization of the cortex can be induced in adulthood. One method is to use the 5-HTT as a biomarker
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