Identifying Molecular Substrates in a Mouse Model of the Serotonin Transporter × Environment Risk Factor for Anxiety and Depression

Carola, Valeria; Frazzetto, Giovanni; Pascucci, Tiziana; Audero, Enrica; Puglisi-Allegra, Stefano; Cabib, Simona; Lesch, Klaus‐Peter; Gross, Cornelius

doi:10.1016/j.biopsych.2007.08.013

Cited by 129 publications

(116 citation statements)

References 39 publications

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“…Similarly, SSRI-induced increases in serum BDNF levels have been detected in depressed patients [32]. Furthermore, SERT heterozygous null mice subjected to poor maternal care show elevated hippocampal BDNF mRNA levels relative to wild type controls undergoing identical experimental procedures [33]. Our data of slightly increased BDNF protein in the hippocampus of SERT-deficient mice seems to fit with these findings.…”

Section: Discussionsupporting

confidence: 82%

Increased brain-derived neurotrophic factor (BDNF) protein concentrations in mice lacking brain serotonin

Kronenberg

Mosienko

Gertz

et al. 2015

Eur Arch Psychiatry Clin Neurosci

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The interplay between BDNF signaling and the serotonergic system remains incompletely understood. Using a highly sensitive enzyme-linked immunosorbent assay, we studied BDNF concentrations in hippocampus and cortex of two mouse models of altered serotonin signaling: tryptophan hydroxylase (Tph)2-deficient (Tph2 -/-) mice lacking brain serotonin and serotonin transporter (SERT) deficient (SERT -/-) mice lacking serotonin re-uptake. Surprisingly, hippocampal BDNF was significantly elevated in Tph2 -/-mice, whereas no significant changes were observed in SERT -/-mice. Furthermore, BDNF levels were increased in the prefrontal cortex of Tph2 -/-but not of SERT -/-mice. Our results emphasize the interaction between serotonin signaling and BDNF. Complete lack of brain serotonin induces BDNF expression.

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Section: Discussionsupporting

confidence: 82%

Increased brain-derived neurotrophic factor (BDNF) protein concentrations in mice lacking brain serotonin

Kronenberg

Mosienko

Gertz

et al. 2015

Eur Arch Psychiatry Clin Neurosci

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“…Consistent with previous data (Carola et al, 2008;Murphy and Lesch, 2008), 5-HTT+/-mice showed significantly reduced serotonin turnover (ratio of 5-hydroxyindole acetic acid to serotonin: 5-HIAA/5-HT) compared with wild-type mice in all three regions (Fig. 6).…”

Section: Decreased Serotonin Turnover In the Frontal Cortex Of Stresssupporting

confidence: 92%

“…These mice show an altered ability to cope with stress, and increased anxiety and depression-like behaviors (Wellman et al, 2007;Holmes et al, 2002;Holmes et al, 2003;Jansen et al, 2010). 5-HTT knockout mutations have also been shown to moderate the adaptive response to early adverse environmental factors Heiming et al, 2009) and poor maternal care (Carola et al, 2008). The latter study used heterozygous 5-HTT knockout mice (having a 50% gene dose-dependent reduction of 5-HTT expression) and found that, although these mice did not show behavioral deficits when raised by mothers providing high maternal care, they developed increased anxiety and depression-related behavior in adulthood when raised by mothers providing poor maternal care.…”

Section: Discussionmentioning

confidence: 99%

Increased vulnerability to psychosocial stress in heterozygous serotonin transporter knockout mice

Bartolomucci

Carola

Pascucci

et al. 2010

Disease Models &Amp; Mechanisms

Self Cite

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Epidemiological evidence links exposure to stressful life events with increased risk for mental illness. However, there is significant individual variability in vulnerability to environmental risk factors, and genetic variation is thought to play a major role in determining who will become ill. Several studies have shown, for example, that individuals carrying the S (short) allele of the serotonin transporter (5-HTT) gene-linked polymorphic region (5-HTTLPR) have an increased risk for major depression following exposure to stress in adulthood. Identifying the molecular mechanisms underlying this gene-by-environment risk factor could help our understanding of the individual differences in resilience to stress. Here, we present a mouse model of the 5-HTT-by-stress risk factor. Wild-type and heterozygous 5-HTT knockout male mice were subjected to three weeks of chronic psychosocial stress. The 5-HTT genotype did not affect the physiological consequences of stress as measured by changes in body temperature, body weight gain and plasma corticosterone. However, when compared with wild-type littermates, heterozygous 5-HTT knockout mice experiencing high levels of stressful life events showed significantly depressed locomotor activity and increased social avoidance toward an unfamiliar male in a novel environment. Heterozygous 5-HTT knockout mice exposed to high stress also showed significantly lower levels of serotonin turnover than wild-type littermates, selectively in the frontal cortex, which is a structure that is known to control fear and avoidance responses, and that is implicated in susceptibility to depression. These data may serve as a useful animal model for better understanding the increased vulnerability to stress reported in individuals carrying the 5-HTTLPR S allele, and suggest that social avoidance represents a behavioral endophenotype of the interaction between 5-HTT and stress

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“…Both short alleles/deleted genes and early adversity, especially when they occurred in combination, promoted depressive-like and anxiety-like behaviour. Carola et al [57] reported, for example, that heterozygous 5-HTT knockout mice showed a more pronounced increase in anxiety-related behaviour after the experience of low maternal care than did wild-type mice. Further, when lactating mice lived in a threatening environment during pregnancy and lactation, offspring showed increased anxiety-like behaviour and reduced exploratory locomotion compared with offspring of mothers who lived in a safe environment, and these effects were most pronounced in homozygous 5-HTT knockout mice when compared with wild-types [58].…”

Section: The Shaping Of Behavioural Profiles During Early Phases Of Lifementioning

confidence: 99%

Behavioural profiles are shaped by social experience: when, how and why

Sachser

Kaiser

Hennessy

2013

Phil. Trans. R. Soc. B

129

158

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The comprehensive understanding of individual variation in behavioural profiles is a current and timely topic not only in behavioural ecology, but also in biopsychological and biomedical research. This study focuses on the shaping of behavioural profiles by the social environment in mammals. We review evidence that the shaping of behavioural profiles occurs from the prenatal phase through adolescence and beyond. We focus specifically on adolescence, a sensitive phase during which environmental stimuli have distinctive effects on the modulation of behavioural profiles. We discuss causation, in particular, how behavioural profiles are shaped by social stimuli through behavioural and neuroendocrine processes. We postulate a central role for maternal hormones during the prenatal phase, for maternal behaviour during lactation and for the interaction of testosterone and stress hormones during adolescence. We refer to evolutionary history and attempt to place developmental shaping into broader evolutionary historical trends. Finally, we address survival value. We argue that the shaping of behavioural profiles by environmental stimuli from the prenatal phase through adolescence represents an effective mechanism for repeated and rapid adaptation during the lifetime. Notably, the adolescent phase may provide a last chance for correction if the future environment deviates from that predicted in earlier phases.

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Identifying Molecular Substrates in a Mouse Model of the Serotonin Transporter × Environment Risk Factor for Anxiety and Depression

Cited by 129 publications

References 39 publications

Increased brain-derived neurotrophic factor (BDNF) protein concentrations in mice lacking brain serotonin

Increased brain-derived neurotrophic factor (BDNF) protein concentrations in mice lacking brain serotonin

Increased vulnerability to psychosocial stress in heterozygous serotonin transporter knockout mice

Behavioural profiles are shaped by social experience: when, how and why

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