The Role of Central Serotonin Neurons and 5-HT Heteroreceptor Complexes in the Pathophysiology of Depression: A Historical Perspective and Future Prospects.

Dasiel O Borroto-Escuela,Maria Lindskog,Harriët Schellekens,Minerva Crespo-Ramirez,Barbara Chruścicka,Juan C Hernández-Mondragón,Patrizia Ambrogini,Miguel Perez De La Mora,Kjell Fuxe

doi:10.3390/ijms22041927

Abstract

Serotonin communication operates mainly in the extracellular space and cerebrospinal fluid (CSF), using volume transmission with serotonin moving from source to target cells (neurons and astroglia) via energy gradients, leading to the diffusion and convection (flow) of serotonin. One emerging concept in depression is that disturbances in the integrative allosteric receptor–receptor interactions in highly vulnerable 5-HT1A heteroreceptor complexes can contribute to causing major depression and become novel targets for the treatment of major depression (MD) and anxiety. For instance, a disruption and/or dysfunction in the 5-HT1A-FGFR1 heteroreceptor complexes in the raphe-hippocampal serotonin neuron systems can contribute to the development of MD. It leads inter alia to reduced neuroplasticity and potential atrophy in the raphe-cortical and raphe-striatal 5-HT pathways and in all its forebrain networks. Reduced 5-HT1A auto-receptor function, increased plasticity and trophic activity in the midbrain raphe 5-HT neurons can develop via agonist activation of allosteric receptor–receptor interactions in the 5-HT1A-FGFR1 heterocomplex. Additionally, the inhibitory allosteric receptor–receptor interactions in the 5-HT1AR-5-HT2AR isoreceptor complex therefore likely have a significant role in modulating mood, involving a reduction of postjunctional 5-HT1AR protomer signaling in the forebrain upon activation of the 5-HT2AR protomer. In addition, oxytocin receptors (OXTRs) play a significant and impressive role in modulating social and cognitive related behaviors like bonding and attachment, reward and motivation. Pathological blunting of the OXTR protomers in 5-HT2AR and especially in 5-HT2CR heteroreceptor complexes can contribute to the development of depression and other types of psychiatric diseases involving disturbances in social behaviors. The 5-HTR heterocomplexes are novel targets for the treatment of MD.

Highlights

In the seminal thesis by Kjell Fuxe on “Evidence for the existence of monoamine neurons in the central monoamine neurons” in 1965 (Karolinska Institutet) [1], we identified the serotonin brain stem neurons [1,2,3] using the Falck–Hillarp fluorescence method
We introduce a novel hypothesis that a few of these 5-HTR heterocomplexes can contribute to depression by changing their densities and/or allosteric receptor–receptor interactions in the plasma membrane in this disease [32]
The inhibitory allosteric receptor–receptor interactions in the 5-HT1AR-5-HT2AR isoreceptor complex likely have a significant role in modulating mood, involving a reduction of postjunctional 5-HT1AR protomer signaling in the forebrain upon activation of the 5-HT2AR protomer (Figure 1)

Summary

Introduction

In the seminal thesis by Kjell Fuxe on “Evidence for the existence of monoamine neurons in the central monoamine neurons” in 1965 (Karolinska Institutet) [1], we identified the serotonin brain stem neurons [1,2,3] using the Falck–Hillarp fluorescence method. 8-OH-DPAT only treatment produced a significant reduction of immobility time, indicating antidepressant effects by the 5-HT1A agonist [42] These antidepressant actions observed in SD rats were associated with significant increases in the density of the 5-HT1AR-FGFR1 complexes in the pyramidal cell layer of the CA2 and CA3 areas and in the dorsal raphe. The mechanism for such marked differences between both strains is not known but it is proposed that specific conformational changes may have developed in 5-HT1AR and/or the FGFR1 in the FSL strain in comparison to the SD rats, possibly related to a different competing balance with other types of receptors/protein complexes (Figure 1) This biochemical change alters their ability to form single or combined agonist-induced changes in the density of 5-HT1AR-FGFR1 heteroreceptor complexes in the dorsal hippocampus in the FSL strain vs the SD control rats. The decline in the formation of hippocampal 5-HT1AR-FGFR1 complexes in FSL rats upon combined treatment with FGF2 and the 5-HT1A agonist may be related to increased competition with the induced formation of FGFR2-5-HT1A, FGFR3-5-HT1A and FGFR4-5-HT1A complexes in the hippocampus

A Novel Hypothesis on Depression

OXTR-5-HT2AR Heteroreceptor Complexes

OXTR-5-HT2CR Heteroreceptor Complexes

Conclusions