Opinion
Serotonin transporter gene, stress and raphe–raphe interactions: a molecular mechanism of depression

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Reports of gene–environment interactions (GxE) between the serotonin transporter gene and stress on risk of depression have generated both excitement and controversy. The controversy persists in part because a mechanistic account of this GxE on serotonergic neurotransmission and risk of depression has been lacking. In this Opinion, we draw on recent discoveries in the functional neuroanatomy of the serotonergic dorsal raphe nucleus (DR) to propose such a mechanistic account. We argue that genetically produced variability in serotonin reuptake during stressor-induced raphe–raphe interactions alters the balance in the amygdala-ventromedial prefrontal cortex (VMPFC)-DR circuitry underlying stressor reactivity and emotion regulation. In particular, the recently characterized stressor-responsive serotonergic interneurons originating from the dorsolateral DR may hold a key to unlocking the GxE mechanism of depression.

Introduction

Exposure to stressors is a primary risk factor for depression. However, whereas some individuals who experience severe life stress go on to develop the illness, others appear resilient to it. A mechanistic, neurobiological account of these individual differences in susceptibility to depression could not only inform our understanding of the illness, but also lead to more effective treatments in the clinic. One framework within which to tackle this problem is that of GxE (see Glossary), which holds that the impact of environmental stressors on risk of depression is modulated by genetic variation, particularly in genes related to brain function and stress response. In particular, increasing evidence from both animal studies [1] and human neuroimaging studies [2] suggests that genetic variation in the serotonin system affects the stress response and risk of depression through the critical brain circuitry underlying stressor reactivity and the regulation of emotion, which encompasses the amygdala, the VMPFC and the dorsal raphe nucleus (DR) [3].

Serotonin (or 5-hydroxytryptamine, 5-HT) is a major modulatory neurotransmitter in the mammalian brain. It is known to regulate behavioral and physiological responses to environmental stressors [4], and has long been implicated in the pathophysiology of depression 5, 6. A prominent candidate in GxE research on depression has been the serotonin transporter. The serotonin transporter protein (5-HTT, SERT), encoded by the serotonin transporter gene (SLC6A4), is responsible for reuptake of serotonin from the extracellular space into presynaptic neurons, and serves as a key regulator of serotonergic signaling. Importantly, the promoter region of the gene harbors a 44 base pair insertion/deletion polymorphism, referred to as the 5-HTT-linked polymorphic region (5-HTTLPR), with the short allele (S) less efficiently transcribed than the long allele (L) in human cell lines in vitro 7, 8, 9 and in post mortem human brains [10] (conflicting findings [11] are possibly due to other, unmeasured functional variants in the same gene 12, 13). A seminal study by Caspi and colleagues [14] demonstrated that the 5-HTTLPR genotype modulates the impact of stress on the risk of depression. In the presence of childhood maltreatment or stressful life events, S/S homozygotes were at a higher risk of developing depressive symptoms compared to L/L homozygotes, with S/L heterozygotes at an intermediate level of risk. These findings have been replicated in a number of studies [15] and supported by a recent meta-analysis [16]. However, several troubling non-replications have also been reported [15], generating considerable controversy in the field [17].

This controversy persists in part because a simple, mechanistic account of exactly how environmental stressors interact with the serotonin transporter genotype to affect serotonergic neurotransmission and risk of depression has been lacking. In this Opinion, we draw on recent advances in understanding of the functional neuroanatomy of the central serotonin system to propose such a mechanistic account. More specifically, we propose a model for how genetically produced variability in serotonin reuptake during stressor-induced raphe–raphe interactions may alter the balance in the amygdala-VMPFC-DR circuitry. Admittedly, much more complex neurobiological models – reflecting the mechanistic interactions of multiple environmental factors (both positive and negative), multiple genes, multiple neurotransmitter systems and multiple brain circuits – will be required to explain all of the nuances and controversies in GxE research on depression. Nevertheless, the proposed model represents an advance in that direction. We conclude with a discussion of the implications and future research directions, including how the proposed model fits into a broader theoretical framework of biological susceptibility to the environment 18, 19, 20.

Section snippets

Serotonergic circuitry

The largest group of serotonergic neurons in the brain originates from the DR in the midbrain and pons. From the DR, the serotonergic neurons project to nearly every area of the forebrain. The DR also receives inputs from some of its projection regions, including the amygdala and the VMPFC, forming feedback loops that are thought to be critical for reactivity to stressors and regulation of emotion [21]. However, not all serotonergic neurons in the DR are projection neurons. To the contrary, the

Concluding remarks

In summary, we have proposed a mechanistic account of the GxE of the 5-HTTLPR and stress on serotonergic neurotransmission and risk of depression. We argue that genetically produced variability in serotonin reuptake during stressor-induced raphe–raphe interactions alters the balance in the critical amygdala-VMPFC-DR circuitry underlying reactivity to stressors and regulation of emotion. Over time, via activity-dependent synaptic plasticity at the glutamatergic synapses in the amygdala [56]

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