Genetic variation in cortico-amygdala serotonin function and risk for stress-related disease

Abstract

The serotonin system is strongly implicated in the pathophysiology and therapeutic alleviation of stress-related disorders such as anxiety and depression. Serotonergic modulation of the acute response to stress and the adaptation to chronic stress is mediated by a myriad of molecules controlling serotonin neuron development (Pet-1), synthesis (tryptophan hydroxylase 1 and 2 isozymes), packaging (vesicular monoamine transporter 2), actions at presynaptic and postsynaptic receptors (5-HT1A, 5-HT1B, 5-HT2A, 5-HT2C, 5-HT3A, 5-HT4, 5-HT5A, 5-HT6, 5-HT7), reuptake (serotonin transporter), and degradation (monoamine oxidase A). A growing body of evidence from preclinical rodents models, and especially genetically modified mice and inbred mouse strains, has provided significant insight into how genetic variation in these molecules can affect the development and function of a key neural circuit between the dorsal raphe nucleus, medial prefrontal cortex and amygdala. By extension, such variation is hypothesized to have a major influence on individual differences in the stress response and risk for stress-related disease in humans. The current article provides an update on this rapidly evolving field of research.

Fig. 1

Major molecular components of the serotonin system. The serotonin system is shaped during ontogeny by various molecules including the peripheral synthesizing enzyme tryptophan hydroxylase 1 (TPH1), the serotonin neuron precursor PET-1, the serotonin transporter (SERT) and serotonin degrading enzyme monoamine oxidase A (MAOA), and the 5-HT1A-R receptor subtype. Within the adult pre-synaptic neuron, serotonin is synthesized by the rate-limiting enzyme tryptophan hydroxylase 2 (TPH2) and packaged and transported via vesicular monoamine transporter 2 (VMAT2) to the synapse for release. Following release, extracellular concentrations of serotonin of regulated by SERT-mediated reuptake and by pre-synaptic autoreceptors at both terminals (5-HT1B-R) and soma (5-HT1A-R). Internalized serotonin is deaminated by MAOA. Extracellular serotonin acts on multiple post-synaptic receptor subtypes located synaptically, as in 5-HT1A-R, 5-HT2C-R, and 5-HT3A-R, as well as extra-synaptically, as may be the case for 5-HT2A-R. The 5-HT4-R, 5-HT5A-R, 5-HT6-R, and 5-HT7-R receptor subtypes are also important functional components of the system these are not depicted here for the sake of clarity.

Fig. 2

Approximate genomic location of serotonin system genes implicated in stress-related phenotypes in the murine genome. Htr1a = 5-HT1A receptor (13 58.0 centimorgans (cM)), Htr1b = 5-HT1B receptor (9 46.0 cM), Htr2a = 5-HT2A receptor (14 41.5 cM), Htr2c = 5-HT2C receptor (X 66.15 cM), Htr3a = 5-HT3A receptor (19 A5.3), Htr4 = 5-HT4 receptor (18 D3), Htr5a = 5-HT5A receptor (5 15.0 cM), Htr6 = 5-HT6 receptor (4 64.9 cM), Htr7 = 5-HT7 receptor (19 33.0 cM), Maoa = monoamine oxidase A (X 5.2 cM), Slc6a4 = serotonin transporter (11 42.0 cM), Slc18a2 = vesicular monoamine transporter 2 (19 D3), Tph1 = tryptophan hydroxylase 1 (7 23.5 cM), Tph2 = tryptophan hydroxylase 2 (10 D2).

Fig. 3

Localization of 5-HT1A-R, 5-HT1B-R, 5-HT2A-R, 5-HT2C-R, and 5-HT3A-R serotonin receptor subunits in the DRN-mPFC-amygdala circuit. These receptor subtypes exhibit a complex and often overlapping pattern of localization within the circuit. DRN = dorsal raphe nucleus, mPFC = medial prefrontal cortex.