The brain neurotransmitter serotonin is involved in the regulation of aggressive behavior. The main factor determining the brain serotonin level is the activity of the rate‐limiting enzyme in the biosynthesis of the neurotransmitter – tryptophan hydroxylase isoform (TPH) 2 encoded by the Tph2 gene. Recently the C1473G single‐nucleotide polymorphism in the Tph2 gene was reported. Here we study the C1473G polymorphism in 10 inbred mouse strains (C57BL/6J, AKR/J, DD/He, C3H/HeJ, YT/Y, BALB/cJLac, CC57BR/Mv and A/He) and demonstrate the association of the polymorphism with brain TPH activity and intermale aggressiveness. TPH activity in the midbrain of mice homozygous for the 1473C allele was higher than that in mice carrying 1473G alleles. A close association of the 1473C allele with increased number of attacks towards another male was found. The results support a link between the C1473G polymorphism in Tph2 gene, trypthophan hydroxylase activity and intensity of intermale aggression.

The serotonergic system and in particular serotonin 1A receptor (5-HT1AR) are implicated in major depressive disorder (MDD). Here we demonstrated that 5-HT1AR is palmitoylated in human and rodent brains, and identified ZDHHC21 as a major palmitoyl acyltransferase, whose depletion reduced palmitoylation and consequently signaling functions of 5-HT1AR. Two rodent models for depression-like behavior show reduced brain ZDHHC21 expression and attenuated 5-HT1AR palmitoylation. Moreover, selective knock-down of ZDHHC21 in the murine forebrain induced depression-like behavior. We also identified the microRNA miR-30e as a negative regulator of Zdhhc21 expression. Through analysis of the post-mortem brain samples in individuals with MDD that died by suicide we find that miR-30e expression is increased, while ZDHHC21 expression, as well as palmitoylation of 5-HT1AR, are reduced within the prefrontal cortex. Our study suggests that downregulation of 5-HT1AR palmitoylation is a mechanism involved in depression, making the restoration of 5-HT1AR palmitoylation a promising clinical strategy for the treatment of MDD.

Serotonin (5-hydroxytryptamine or 5-HT) is an important neurotransmitter regulating a wide range of physiological and pathological functions via activation of heterogeneously expressed 5-HT receptors. Besides the important role of 5-HT receptors in the pathogenesis of depressive disorders and in their clinical medications, underlying mechanisms are far from being completely understood. This review focuses on possible cross talk between two serotonin receptors, 5-HT1A and the 5-HT7 . Although these receptors are highly co-expressed in brain regions implicated in depression, and most agonists developed for the 5-HT1A or 5-HT7 receptors have cross-reactivity, their functional interaction has not been yet established. It has been recently shown that 5-HT1A and 5-HT7 receptors form homo- and heterodimers both in vitro and in vivo. From the functional point of view, heterodimerization has been shown to play an important role in regulation of receptor-mediated signaling and internalization, suggesting the implication of heterodimerization in the development and maintenance of depression. Interaction between these receptors is also of clinical interest, because both receptors represent an important pharmacological target for the treatment of depression and anxiety.

Neurotrophic factors play a key role in development, differentiation, synaptogenesis, and survival of neurons in the brain as well as in the process of their adaptation to external influences. The serotonergic (5-HT) system is another major factor in the development and neuroplasticity of the brain. In the present review, the results of our own research as well as data provided in the corresponding literature on the interaction of brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) with the 5-HT-system of the brain are considered. Attention is given to comparison of BDNF and GDNF, the latter belonging to a different family of neurotrophic factors and being mainly considered as a dopaminergic system controller. Data cited in this review show that: (i) BDNF and GDNF interact with the 5-HT-system of the brain through feedback mechanisms engaged in autoregulation of the complex involving 5-HT-system and neurotrophic factors; (ii) GDNF, as well as BDNF, stimulates the growth of 5-HT neurons and affects the expression of key genes of the brain 5-HT-system - those coding tryptophan hydroxylase-2 and 5-HT and 5-HT receptors. In turn, 5-HT affects the expression of genes that control BDNF and GDNF in brain structures; (iii) the difference between BDNF and GDNF is manifested in different levels and relative distribution of expression of these factors in brain structures (BDNF expression is highest in hippocampus and cortex, GDNF expression in the striatum), in varying reaction of 5-HT receptors on BDNF and GDNF administration, and in different effects on certain types of behavior.

Among an impressive variety of identified serotonin receptors, 5-HT1A attracts particular attention due to its central role in the regulation of 5-HT-ergic neurotransmission and the data on its involvement in the mechanisms of stress response, aggressive behavior, anxiety, and depression. This review concentrates on the cross-regulation between 5-HT receptors and the implication of the 5-HT1A receptor in the genetic control of 5-HT-related behavior. Specifically, it describes the (1) functional interactions between 5-HT1A, 5-HT2A, 5-HT3, and 5-HT7 receptors; (2) cross-talk between 5-HT1A receptor and genes encoding key members of the brain 5-HT system; (3) implication of the 5-HT1A receptor in natural hibernation and genetic predisposition to different kinds of defensive behavior; and (4) role of 5-HT1A autoreceptors and heteroreceptors in anxiety, depression, and suicide, and in the antidepressant effect of serotonin reuptake inhibitors. This review provides converging lines of evidence that the 5-HT1A receptor contributes to the action of other 5-HT receptors, modulating their effect on behavior, and describes new data on the unique role of the 5-HT1A receptor in the indirect regulation of gene expression and in the autoregulation of the brain 5-HT system.