The role of 5-HT receptors in depression

Christine N Yohn, Mark M Gergues, Benjamin Adam Samuels, Christine N Yohn, Mark M Gergues, Benjamin Adam Samuels

Abstract

Depression is a polygenic and highly complex psychiatric disorder that remains a major burden on society. Antidepressants, such as selective serotonin reuptake inhibitors (SSRIs), are some of the most commonly prescribed drugs worldwide. In this review, we will discuss the evidence that links serotonin and serotonin receptors to the etiology of depression and the mechanisms underlying response to antidepressant treatment. We will then revisit the role of serotonin in three distinct hypotheses that have been proposed over the last several decades to explain the pathophysiology of depression: the monoamine, neurotrophic, and neurogenic hypotheses. Finally, we will discuss how recent studies into serotonin receptors have implicated specific neural circuitry in mediating the antidepressant response, with a focus being placed on the hippocampus.

Keywords: 5-HT1A receptor; Adult neurogenesis; Antidepressant; Dentate gyrus; Depression; Hippocampus; Serotonin.

Figures

Fig. 1
Fig. 1
A proposed model of the hippocampal microcircuit underlying the effects of increased serotonin on the dentate gyrus. First, chronic SSRI administration increases 5-HT levels, which results in activation of 5-HTRs on dentate gyrus granule cells. Activation of 5HT-1ARs on mature granular cells ultimately results in release of downstream growth factors such as BDNF, VEGF, and others, which bind to receptors on neural precursor cells (NPCs) in the subgranular zone. NPCs then proliferate and differentiate into young adult born granule cells (abGCs), which will begin to migrate, mature, and finally integrate into the granule cell layer. However, the young abGCs have distinct plasticity properties from the mature dentate gyrus granule cells and activate local GABAergic interneurons to evoke strong inhibitory input to the mature granule cells
Fig. 2
Fig. 2
The expression of 5-HT1A receptors along the dorsoventral axis of the hippocampus in a rodent brain. 5-HT1AR expression is highest in dorsal CA1 and ventral dentate gyrus. The dorsal and ventral hippocampus participate in distinct circuitry, with the ventral hippocampus projecting to limbic structures. Therefore, 5-HT1ARs on dentate gyrus granule cells are well positioned to exert an influence on mood related behaviors

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