Inactivation of 5HT Transport in Mice: Modeling Altered 5HT Homeostasis Implicated in Emotional Dysfunction, Affective Disorders, and Somatic Syndromes

Lesch, K.P.; Mößner, Rainald

doi:10.1007/3-540-29784-7_18

Cited by 36 publications

(25 citation statements)

References 143 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Studies with knockout mice support this hypothesis. If the mutation is viable, it would induce large modifications with homeostatic consequences on neurodevelopment (Lesch and Mössner 2006). Additionally, the early role of serotonin and its receptors in the course of prenatal development, as well as its influence on the morphogenesis of the brain, suggests that serotonin influences the development and brain maturation of mammals before taking its role as a neurotransmitter.…”

Section: Biological Embeddingmentioning

confidence: 99%

Stress and Vulnerability: A Developing Model for Suicidal Risk

López-Castromán

Olié

Courtet

2014

Suicide: Phenomenology and Neurobiology

View full text Add to dashboard Cite

A large body of research built over the last few decades examines the interaction between stressful events and vulnerability traits to explain how a person becomes suicidal. This stress-diathesis model has been extremely fruitful to improve our understanding of suicidal behavior, but recent findings suggest that interactions could be more complex than expected. Indeed, environmental insults during pregnancy, childhood, or adolescence induce neurodevelopmental changes that increase the vulnerability for suicidal behavior in later life. In this chapter, we will outline the significance of recent neurodevelopmental findings for the stressvulnerability factors of suicidal behavior. The coherence and applicability of an integrative neurodevelopmental model of suicidal behavior will be discussed in the light of current research concerning genetics, neuroimaging, and neuropsychology, and the new classification systems. IntroductionDespite treatment and prevention advances on major psychiatric disorders, suicidal behavior still constitutes a major public health problem. Research into this behavior has increased exponentially during the last decade, and a complex network of factors, both predisposing and triggering the suicidal acts, is being unraveled. This dynamic network connects mental disorders, life experiences, social and familial interactions, physical illness, and neurobiology into what is known as the suicidal process. However, until a deeper understanding of the relationships between these factors is developed, crucial issues such as yielding an accurate prediction of future suicidal acts or determining the best treatment for suicidal patients remain distant.

show abstract

Section: Biological Embeddingmentioning

confidence: 99%

Stress and Vulnerability: A Developing Model for Suicidal Risk

López-Castromán

Olié

Courtet

2014

Suicide: Phenomenology and Neurobiology

View full text Add to dashboard Cite

show abstract

“…The evidence for epigenetic inheritance of anxiety and depression-like behaviour underscores the view that environmental influences can persistently remodel circuits in the brain during early development. 5-Htt deficient and other genetically modified mice will therefore be essential for the dissection of the molecular and neural mechanisms of epigenetic processes and of the neurodevelopmental-behavioural interface (Lesch and M€ ossner 2006). Increased social avoidance (a), decreased locomotor activity, and increased serotonin concentrations (c) in the frontal cortex of mice in 5-Htt þ/À mice receiving highest aggression in the residentintruder paradigm, whereas both wildtype and 5-Htt þ/À mice show increased body weight, body temperature, aggression-induced hyperthermia, and corticosterone plasma concentrations following social defeat (b)…”

Section: Chronic Psychosocial Stress In Adulthoodmentioning

confidence: 99%

“…In the years following the first reports linking 5-HTT variation with anxiety-and aggression-related traits, numerous clinical entities have been studied for association with disorders characterized to a large extent by emotional dysregulation, including depression, bipolar affective disorder, attention-deficit/hyperactivity disorder, alcohol dependence, suicide, eating disorders and autism or disorders related to morphogenetic actions of 5-HT in other organ systems such as heart, blood vessels, bowel, and bone (Lesch and M€ ossner 2006;Murphy et al 2004. Modest effect sizes typical of complex traits, polygenic patterns of inheritance, epistatic and epigenetic interactions and sample heterogeneity across studies are all factors which have led to inconsistent replication and have confounded attempts to reach agreement regarding the role of 5-HTT in the pathophysiology of all these diseases.…”

Section: Introductionmentioning

confidence: 99%

When the Serotonin Transporter Gene Meets Adversity: The Contribution of Animal Models to Understanding Epigenetic Mechanisms in Affective Disorders and Resilience

Lesch

2011

Current Topics in Behavioral Neurosciences

View full text Add to dashboard Cite

Although converging epidemiological evidence links exposure to stressful life events with increased risk for affective spectrum disorders, there is extraordinary interindividual variability in vulnerability to adversity. The environmentally moderated penetrance of genetic variation is thought to play a major role in determining who will either develop disease or remain resilient. Research on genetic factors in the aetiology of disorders of emotion regulation has, nevertheless, been complicated by a mysterious discrepancy between high heritability estimates and a scarcity of replicable gene-disorder associations. One explanation for this incongruity is that at least some specific gene effects are conditional on environmental cues, i.e. gene-by-environment interaction (G × E) is present. For example, a remarkable number of studies reported an association of variation in the human serotonin (5-HT) transporter gene (SLC6A4, 5-HTT, SERT) with emotional and cognitive traits as well as increased risk for depression in interaction with psychosocial adversity. The results from investigations in non-human primate and mouse support the occurrence of G × E interaction by showing that variation of 5-HTT function is associated with a vulnerability to adversity across the lifespan leading to unfavourable outcomes resembling various neuropsychiatric disorders. The neural and molecular mechanisms by which environmental adversity in early life increases disease risk in adulthood are not known but may include epigenetic programming of gene expression during development. Epigenetic mechanisms, such as DNA methylation and chromatin modification, are dynamic and reversible and may also provide targets for intervention strategies (see Bountra et al., Curr Top Behav Neurosci, 2011). Animal models amenable to genetic manipulation are useful in the identification of molecular mechanisms underlying epigenetic programming by adverse environments and individual differences in resilience to stress. Therefore, deeper insight into the role of epigenetic regulation in the process of neurodevelopmental programmes is likely to result in early diagnosis of affective spectrum disorders and will contribute to the design of innovative treatments targeting neural pathways that foster resilience.

show abstract

“…One of the models is the 5-HT transporterdeficient mouse (5-HTT -/-). 50,51 By mediating 5-HT reuptake in the nerve terminal (and other parts of the 5-HT neuron), 5-HTT fine-tunes the magnitude and duration of serotoninergic signaling, 52,53 which makes it the target for many antidepressant drugs, including the SSRIs. 54 These animals exhibit major adaptive changes in 5-HT neurotransmission when compared with their wild-type controls.…”

Section: Animal Models Of Depression: Genetically Modified Animal Modelsmentioning

confidence: 99%

Animal models as tools to study the pathophysiology of depression

Abelaira

Réus

Quevedo

2013

Rev. Bras. Psiquiatr.

199

116

View full text Add to dashboard Cite

The incidence of depressive illness is high worldwide, and the inadequacy of currently available drug treatments contributes to the significant health burden associated with depression. A basic understanding of the underlying disease processes in depression is lacking; therefore, recreating the disease in animal models is not possible. Popular current models of depression creatively merge ethologically valid behavioral assays with the latest technological advances in molecular biology. Within this context, this study aims to evaluate animal models of depression and determine which has the best face, construct, and predictive validity. These models differ in the degree to which they produce features that resemble a depressive-like state, and models that include stress exposure are widely used. Paradigms that employ acute or sub-chronic stress exposure include learned helplessness, the forced swimming test, the tail suspension test, maternal deprivation, chronic mild stress, and sleep deprivation, to name but a few, all of which employ relatively short-term exposure to inescapable or uncontrollable stress and can reliably detect antidepressant drug response.

show abstract

Inactivation of 5HT Transport in Mice: Modeling Altered 5HT Homeostasis Implicated in Emotional Dysfunction, Affective Disorders, and Somatic Syndromes

Cited by 36 publications

References 143 publications

Stress and Vulnerability: A Developing Model for Suicidal Risk

Stress and Vulnerability: A Developing Model for Suicidal Risk

When the Serotonin Transporter Gene Meets Adversity: The Contribution of Animal Models to Understanding Epigenetic Mechanisms in Affective Disorders and Resilience

Animal models as tools to study the pathophysiology of depression

Contact Info

Product

Resources

About