Inhibition of Serotonin But Not Norepinephrine Transport during Development Produces Delayed, Persistent Perturbations of Emotional Behaviors in Mice

Ansorge, Mark S.; Morelli, Emanuela; Gingrich, Jay A.

doi:10.1523/jneurosci.3973-07.2008

Cited by 284 publications

(289 citation statements)

References 60 publications

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“…A tryptophan (the precursor of serotoninF5-HT) metabolic pathway in the placenta (Bonnin et al, 2011) reflects the potential importance of extra-embryonically derived 5-HT in modulating developmental processes such as brain circuit wiring, thus affecting long-term brain function. This concept is consistent with classic genetic (5-HT1A knockout) and pharmacological (SSRI exposure) studies showing that disruption of 5-HT signaling transiently, during a restricted period of pre-or postnatal development, results in long-term behavioral abnormalities, such as increased anxiety in adulthood (Ansorge et al, 2008;Oberlander et al, 2009). Because many 5-HT receptors are expressed early and in complex temporal and spatial patterns during brain development (Bonnin et al, 2006), the full extent of the mechanisms through which disruption of 5-HT signaling leads to adult phenotypes is not yet understood.…”

Section: Placental Source For 5-ht That Tunes Fetal Brain Developmentsupporting

confidence: 86%

Placental Source for 5-HT that Tunes Fetal Brain Development

Bonnin

Levitt

2011

Neuropsychopharmacol

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Section: Placental Source For 5-ht That Tunes Fetal Brain Developmentsupporting

confidence: 86%

Placental Source for 5-HT that Tunes Fetal Brain Development

Bonnin

Levitt

2011

Neuropsychopharmacol

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“…Developmental influence of 5HTT on Npas4 and GABA marker G Guidotti et al forced-swim test (Hansen et al, 1997), anxiety-related behavioral disturbances (Ansorge et al, 2008;Ansorge et al, 2004), and increased REM sleep (Popa et al, 2008) at adulthood. Collectively, these data show that SERT blockade exerts age-dependent effects on behavior (for review see Olivier et al (2010)), leading to a variety of unfavorable outcomes in rodents, which are opposite with respect to the effects produced by SSRIs during adulthood, but comparable to SERT knockout in rodents .…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, serotonin (5-HT) transmission is implicated both in the onset of depression and in the mechanism of action of several antidepressant drugs (Jans et al, 2007). Moreover, findings from genetical and pharmacological studies indicate that serotonin signaling during early life is critically involved in the development of brain circuits that modulate adult emotional behavior (Ansorge et al, 2008;Ansorge et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Developmental Influence of the Serotonin Transporter on the Expression of Npas4 and GABAergic Markers: Modulation by Antidepressant Treatment

Guidotti

Calabrese

Auletta

et al. 2011

Neuropsychopharmacol

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Alterations of the serotonergic system are involved in the pathophysiology of mood disorders and represent an important target for its pharmacological treatment. Genetic deletion of the serotonin transporter (SERT) in rodents leads to an anxious and depressive phenotype, and is associated with reduced neuronal plasticity as indicated by decreased brain-derived neurotrophic factor (Bdnf) expression levels. One of the transcription factors regulating Bdnf is the neuronal PAS domain protein 4 (Npas4), which regulates activitydependent genes and neuroprotection, and has a critical role in the development of GABA synapses. On the basis of these premises, we investigated the expression of Npas4 and GABAergic markers in the hippocampus and prefrontal cortex of homozygous (SERT À/À ) and heterozygous (SERT + /À ) knockout rats, and analyzed the effect of long-term duloxetine treatment on the expression of these targets. We found that Npas4 expression was reduced in both the brain structures of adult SERT + /À and SERT À/À animals. This effect was already present in adolescent SERT À/À , and could be mimicked by prenatal exposure to the antidepressant fluoxetine. Moreover, SERT À/À rats showed a strong impairment of the GABAergic system, as indicated by the reduction of several markers, including the vesicular transporter (Vgat), glutamic acid decarboxylase-67 (Gad67), the receptor subunit GABA A receptor, gamma 2 (GABA A -g2), and calciumbinding proteins that label subgroups of the GABAergic neurons. Interestingly, chronic treatment with the antidepressant duloxetine was able to restore the physiological levels of Npas4 and GABAergic markers in SERT À/À rats, although some differences in the modulation of GABAergic genes exist between hippocampus and prefrontal cortex. Our results demonstrate that SERT knockout rats, an animal model of mood disorders, have reduced Npas4 expression that correlates with decreased expression of Bdnf exon I and IV. These changes lead to an impairment of the GABAergic system that may contribute to the anxious and depressive phenotype associated with inherited SERT downregulation.

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“…A number of observations support this hypothesis. First, treating non-mutant rats and mice with SERT-blocking SRIs such as fluoxetine during the first weeks of life (corresponding to late pregnancy in humans) mimics the increased anxiety-and depression-like phenotype of Slc6a4 knockout (Andersen et al, 2002;Ansorge et al, 2004Ansorge et al, , 2008Feng et al, 2001b;Hilakivi and Hilakivi, 1987;Maciag et al, 2006aMaciag et al, , 2006b). Second, Alexandre and colleagues have shown that either depleting serotonin levels with PCPA or inhibiting 5-HT1A-Rs with WAY 100635 during the first few weeks of life, both of which presumably block some of the actions of excessive neonatal serotonin, is sufficient to rescue some of the depression-related abnormalities in adult SERT knockout mice (Alexandre et al, 2006).…”

Section: Serotonin Reuptakementioning

confidence: 99%

Genetic variation in cortico-amygdala serotonin function and risk for stress-related disease

Holmes

2008

Neuroscience & Biobehavioral Reviews

249

166

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The serotonin system is strongly implicated in the pathophysiology and therapeutic alleviation of stress-related disorders such as anxiety and depression. Serotonergic modulation of the acute response to stress and the adaptation to chronic stress is mediated by a myriad of molecules controlling serotonin neuron development (Pet-1), synthesis (tryptophan hydroxylase 1 and 2 isozymes), packaging (vesicular monoamine transporter 2), actions at presynaptic and postsynaptic receptors (5-HT1A, 5-HT1B, 5-HT2A, 5-HT2C, 5-HT3A, 5-HT4, 5-HT5A, 5-HT6, 5-HT7), reuptake (serotonin transporter), and degradation (monoamine oxidase A). A growing body of evidence from preclinical rodents models, and especially genetically modified mice and inbred mouse strains, has provided significant insight into how genetic variation in these molecules can affect the development and function of a key neural circuit between the dorsal raphe nucleus, medial prefrontal cortex and amygdala. By extension, such variation is hypothesized to have a major influence on individual differences in the stress response and risk for stress-related disease in humans. The current article provides an update on this rapidly evolving field of research.

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Inhibition of Serotonin But Not Norepinephrine Transport during Development Produces Delayed, Persistent Perturbations of Emotional Behaviors in Mice

Cited by 284 publications

References 60 publications

Placental Source for 5-HT that Tunes Fetal Brain Development

Placental Source for 5-HT that Tunes Fetal Brain Development

Developmental Influence of the Serotonin Transporter on the Expression of Npas4 and GABAergic Markers: Modulation by Antidepressant Treatment

Genetic variation in cortico-amygdala serotonin function and risk for stress-related disease

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