5. Recent advances
The heuristic value of a hypothesis often measures itself against the richness, originality and quality of the data it helps to generate. In this sense, the 5-HT hypothesis of depression resists the passage of time considering the wealth of information it continues to generate. This is particularly well illustrated by the articles assembled in this first special issue, subtitled ‘Cellular and molecular mechanisms’.
The first article, by Gaspar & Lillesaar [23], is a broad and up-to-date account of previous and novel data demonstrating diversity in the morphological and functional organization of the brain 5-HT system. These authors recently studied the genetic programming of this system in mice and zebrafish. In both species, 5-HT neurons differ in the transcription factors contributing to their acquisition of a 5-HT identity. For example, there are PET1-dependent and PET1-independent 5-HT neurons in the midbrain raphe of mice, displaying distinct anatomical features. In zebrafish, all raphe neurons express pet1, but Pet1-independent 5-HT cell groups are found in the forebrain. These observations support the view of a number of distinct 5-HT subsystems with unique genetic programming and functions.
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In the next article, Tanaka et al. [24], using in situ hybridization describe the distribution of the mRNA for all 5-HT receptor (Htr) subtypes in mouse hippocampus, excluding Htr6. At the cellular level, their results support the view that several Htr subtypes may be expressed by the same neurons. At the regional level, they report changes in the expression pattern for Htr1a, Htr2a, Htr2c and Htr7 expression along the dorsal-ventral axis of hippocampus. Given the proposed functional differentiation of hippocampus along its long axis, with its dorsal region more involved in cognitive functions and its ventral blade in mood and anxiety, they suggest that 5-HT receptors enriched in the ventral segment, such as Htr1a, Htr2c and Htr7, likely play a role in mood- and anxiety-related behaviour, as well as in the anxiolytic and antidepressant effects of selective 5-HT reuptake inhibitors (SSRIs).
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The review of Albert [25] is a thorough update on recent discoveries in 5-HT1A gene regulation, and its link with psychiatric disorders. It provides a strong argument that dysregulation of 5-HT1A autoreceptor and heteroceptor (genetic or environmental in basis, or both) is a risk factor for depression and anxiety. Although the findings in the literature are not all consistent (animal data are much clearer than the human data), overall the data suggest that upregulation of 5-HT1A autoreceptors and consequent reduction in serotonergic tone may be a risk factor for depression.
In their article, Descarries & Riad [26] summarize their immuno-electron microscopic studies on the trafficking of the 5-HT1A autoreceptor in rats acutely or chronically treated with the prototypic SSRI, fluoxetine (Prozac). These studies have led to the brain imaging demonstration of an internalization of this receptor in the dorsal raphe nucleus of human volunteers administered a single oral dose of Prozac. Preliminary immuno-electron microscopic results are also reported, indicating that upon chronic, but not acute treatment with fluoxetine, the plasma membrane 5-HT transporter, SERT, internalizes and is degraded in both the cell bodies and axon terminals of midbrain 5-HT neurons.
The paper by Lesch et al. [27] analyses the effects of Tph2 gene deletion or inactivation in mice on emotional and aggressive behaviour, and their morphological, neurochemical and functional correlates, in comparison with other genetic mouse models. It provides important insights into the relationship between specific behavioural phenotypes and neurobiological parameters. As several assumed relationships, e.g. between anxiety and depression and 5-HT1A autoreceptor function in depression, do not hold true in this particular model, it is concluded that approaches focusing on TPH2 variants in humans may reveal unexpected aspects of the role of 5-HT in brain development and in disorders characterized by negative emotionality, aggression and antisocial behaviour.
After recapitulating the history of 5-HT implication in depression, with particular emphasis on 5-HT deficiency, the article of Jacobsen et al. [28] presents new evidence that 5-HT biomarker abnormalities associated with depression occur consequent to severely reduced brain levels of extracellular 5-HT in a mouse model of naturalistic 5-HT deficiency, the tryptophan hydroxylase 2 His439 (Tph2KI) knockin mouse. Other studies examining the functional consequences of depression-related TPH2 variants are also reviewed, as growing evidence for an association of functional coding and non-coding polymorphisms in Tph2 with depression and other psychiatric diseases.
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Latapy et al. [29] provide the first description of the behavioural phenotype of mice with a CAMKCRE-mediated knockout of the kinase GSK3β in forebrain pyramidal neurons. These mice show an exaggerated response to amphetamine, reduced anxiety and greater social interactions, but no change in spontaneous locomotion or abnormality in the tail suspension test or the forced swim tests, nor in aversion response to social defeat. In contrast, GSK3β heterozygotes show no change in social interactions and a positive effect on social defeat. Thus, the modulation of behaviour by GSK3 kinases appears dependent on their anatomical location, and hence their specific contribution to the effects of psychiatric drugs.
In contrast to the previous articles on serotonergic mechanisms, the paper by Duman & Li [30] discusses the role in depression of neuronal atrophy owing to stress or reduced growth factor support, and focuses on their studies of the mechanisms underlying the rapid actions of glutamatergic NMDA receptor antagonist, ketamine. Acute treatment with ketamine leads to rapid synaptogenesis and spine formation in the prefrontal cortex via a signalling pathway involving mTOR activation, and can reverse dendrite atrophy induced by chronic stress. These actions correlate with the rapid effects of ketamine on anxiety and depression-like behaviours, and suggest that modulation of the glutamate system at specific sites may provide a new approach to treat depression.
The article by Massart et al. [31] also considers alternatives to the monoamine theory of depression. After an overview of current hypotheses mostly centred on dysfunctions of the hypothalamic-pituitary adrenal axis, circadian rhythms and neuroimmune processes, including a role for epigenetics in depression, it analyses various changes in the expression of genes controlling the activity of the hypothalamic-pituitary-adrenal axis and those involved in epigenetic regulations, which were recently detected in the glucocorticoid receptor-impaired mouse model of depressive disorders.
The last paper of this issue, by Hellström et al. [32], focuses on a model of the role of early life environment in determining adult life stress responsiveness. Maternal licking and grooming of the pups leads to increased levels of hippocampal glucocorticoid receptors via altered epigenetic modifications, including DNA methylation of the hippocampal-specific promoter, increasing negative feedback regulation and reducing stress responsiveness throughout life. This study probes the neurohormonal basis by which licking and grooming or tactile stimulation triggers this pathway and regulates gene expression. These studies implicate both 5-HT and thyroid hormone in early life modifications of hippocampal gene expression by activation of a specific transcription factor, NGFA, and have important implications for the role of early epigenetic and transcriptional modifications in gene-environment interactions.
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