Reduced function of the serotonin transporter is associated with decreased expression of BDNF in rodents as well as in humans

Molteni, Raffaella; Cattaneo, Annamaria; Calabrese, Francesca; Macchi, F.; Olivier, Jocelien; Racagni, Giorgio; Ellenbroek, Bart A.; Gennarelli, Massimo; Riva, Marco A.

doi:10.1016/j.nbd.2009.12.014

Cited by 120 publications

(95 citation statements)

References 56 publications

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“…Conceptually, mild increases in BDNF protein content in SERT -/-mice with reduced serotonin concentrations in brain tissue also fit well with more robust BDNF increases in Tph2 -/-mice that lack brain serotonin completely. However, our results differ somewhat from other studies that found reduced BDNF signaling in the ventral hippocampus and prefrontal cortex of SERT deficient rats [34,35]. Finally, another study of BDNF conducted in SERT +/+ , SERT +/-and SERT -/-mice did not yield any significant differences in BDNF protein levels between genotypes in hippocampus, frontal cortex, and brain stem [36].…”

Section: Discussioncontrasting

confidence: 99%

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: Discussioncontrasting

confidence: 99%

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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“…Interestingly, all these pathologies share the common feature of maladaptive learning. In particular, recent evidences have suggested that abnormal regional-specific BDNF expression contributes to the functional defects observed in drug addiction (Fumagalli et al, 2007) and in depression (Molteni et al, 2009). In this scenario, our data shed new light on the complex role of BDNF in epilepsy and within the striatal microcircuit.…”

Section: Discussionsupporting

confidence: 55%

TrkB/BDNF-Dependent Striatal Plasticity and Behavior in a Genetic Model of Epilepsy: Modulation by Valproic Acid

Ghiglieri

Sgobio

Patassini

et al. 2010

Neuropsychopharmacol

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In mice lacking the central domain of the presynaptic scaffold Bassoon the occurrence of repeated cortical seizures induces cell-typespecific plasticity changes resulting in a general enhancement of the feedforward inhibition within the striatal microcircuit. Early antiepileptic treatment with valproic acid (VPA) reduces epileptic attacks, inhibits the emergence of pathological form of plasticity in fast-spiking (FS) interneurons and restores physiological striatal synaptic plasticity in medium spiny (MS) neurons. Brain-derived neurotrophic factor (BDNF) is a key factor for the induction and maintenance of synaptic plasticity and it is also implicated in the mechanisms underlying epilepsy-induced adaptive changes. In this study, we explore the possibility that the TrkB/BDNF system is involved in the striatal modifications associated with the Bassoon gene (Bsn) mutation. In epileptic mice abnormal striatum-dependent learning was paralleled by higher TrkB levels and an altered distribution of BDNF. Accordingly, subchronic intrastriatal administration of k252a, an inhibitor of TrkB receptor tyrosine kinase activity, reversed behavioral alterations in Bsn mutant mice. In addition, in vitro manipulations of the TrkB/BDNF complex by k252a, prevented the emergence of pathological plasticity in FS interneurons. Chronic treatment with VPA, by reducing seizures, was able to rebalance TrkB to control levels favoring a physiological redistribution of BDNF between MS neurons and FS interneurons with a concomitant recovery of striatal plasticity. Our results provide the first indication that BDNF is involved in determining the striatal alterations occurring in the early-onset epileptic syndrome associated with the absence of presynaptic protein Bassoon.

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“…Accordingly, we used targetdirected mutagenesis to generate SERT-knockout rats (Smits et al, 2006), which present an impaired serotonergic system and are characterized by anxiety-and depressionlike behavioral alterations (Homberg et al, 2007;Kalueff et al, 2010;Olivier et al, 2008). We have previously demonstrated that SERT knockout (SERT À/À ) rats have altered neuronal plasticity, as indicated by the reduction of activity-regulated cytoskeleton associated protein (Arc) and of brain-derived neurotrophic factor (Bdnf) expression levels in the hippocampus and prefrontal cortex (Molteni et al, 2009b;Molteni et al, 2010). Interestingly, long-term treatment with the antidepressant duloxetine was able to normalize the Bdnf expression in both the brain regions .…”

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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Reduced function of the serotonin transporter is associated with decreased expression of BDNF in rodents as well as in humans

Cited by 120 publications

References 56 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

TrkB/BDNF-Dependent Striatal Plasticity and Behavior in a Genetic Model of Epilepsy: Modulation by Valproic Acid

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

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