Lack of promoter IV‐driven BDNF transcription results in depression‐like behavior

Sakata, Kazuko; Jin, Luhong; Jha, Shanker

doi:10.1111/j.1601-183x.2010.00605.x

Cited by 81 publications

(98 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Furthermore, a strong relationship exists between Bdnf and GABA (Yamada et al, 2002). It has recently been demonstrated that promoter IV-driven Bdnf transcription has a critical role in GABAergic transmission (Sakata et al, 2009), and mice with a selective deficiency of promoter-IV-dependent expression of Bdnf show depression-like behavior (Sakata et al, 2010). Collectively, these data support the potential link between Npas4, Bdnf, and GABA in contributing to the phenotypic changes observed in SERT À/À rats.…”

Section: Discussionsupporting

confidence: 68%

“…This led us to hypothesize that the transcription factor Npas4 may be altered in animal models of depression, and may eventually link alterations of neuroplastic markers, such as Bdnf, with an impaired function of the GABAergic system. On this basis, we investigated Npas4 expression in the hippocampus and prefrontal cortex of SERT + /À and SERT À/À rats, which model depression-and anxiety-related dysfunctions in humans, and we analyzed the expression of different GABAergic markers that may represent downstream targets of Npas4 and Bdnf signaling Sakata et al, 2010). Moreover, we investigated the ability of long-term treatment with the serotonin-norepinephrine reuptake inhibitor (SNRI) duloxetine to normalize molecular defects associated with genetic deletion of SERT.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 68%

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

View full text Add to dashboard Cite

show abstract

“…Impaired reversal learning as well as delayed initiation and deficits in response inhibition in the passive avoidance test (44) in BDNF-KIV mice are reminiscent of the slow adaption to rule changes and difficulty in inhibiting previously learned responses in patients with schizophrenia or PFC damage (45,46). Although spatial memory acquisition depends critically on the hippocampus, response learning in a taxon system also requires intact PFC function (21).…”

Section: Discussionmentioning

confidence: 99%

Role of activity-dependent BDNF expression in hippocampal–prefrontal cortical regulation of behavioral perseverance

Sakata

Martinowich²,

Woo

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

119

131

View full text Add to dashboard Cite

Activity-dependent gene transcription, including that of the brainderived neurotrophic factor (Bdnf) gene, has been implicated in various cognitive functions. We previously demonstrated that mutant mice with selective disruption of activity-dependent BDNF expression (BDNF-KIV mice) exhibit deficits in GABA-mediated inhibition in the prefrontal cortex (PFC). Here, we show that disruption of activity-dependent BDNF expression impairs BDNF-dependent late-phase long-term potentiation (L-LTP) in CA1, a site of hippocampal output to the PFC. Interestingly, early-phase LTP and conventional L-LTP induced by strong tetanic stimulation were completely normal in BDNF-KIV mice. In parallel, attenuation of activity-dependent BDNF expression significantly impairs spatial memory reversal and contextual memory extinction, two executive functions that require intact hippocampal-PFC circuitry. In contrast, spatial and contextual memory per se were not affected. Thus, activity-dependent BDNF expression in the hippocampus and PFC may contribute to cognitive and behavioral flexibility. These results suggest distinct roles for different forms of L-LTP and provide a link between activity-dependent BDNF expression and behavioral perseverance, a hallmark of several psychiatric disorders.

show abstract

Section: Florian Duclot and Mohamed Kabbaj*mentioning

confidence: 99%

“…This structure allows for a very complex regulation of the Bdnf gene transcription in a time-, tissue-and stimulus-specific manner, which are all critical parameters for BDNF regulation of neuronal plasticity (Park and Poo, 2013). Notably, mice lacking promoter-4-driven Bdnf transcription show depression-like behaviors under stressful conditions (Sakata et al, 2010), suggesting a promoter-specific involvement of Bdnf in the response to stress.In humans, however, numerous studies report reduced serum BDNF levels in depressed patients, which are then normalized to the levels of healthy controls by antidepressant treatment (BocchioChiavetto et al, 2006; Brunoni et al, 2008; Hoyer et al, 2012;Pallavi et al, 2013;Sen et al, 2008). However, serum BDNF levels do not systematically correlate with the severity of depressive symptoms, which questions its use as an accurate biomarker for depression (Molendijk et al, 2011;Molendijk et al, 2014).…”

mentioning

confidence: 99%

Epigenetic mechanisms underlying the role of brain-derived neurotrophic factor in depression and response to antidepressants

Duclot

Kabbaj

2015

Journal of Experimental Biology

View full text Add to dashboard Cite

Major depressive disorder (MDD) is a devastating neuropsychiatric disorder encompassing a wide range of cognitive and emotional dysfunctions. The prevalence of MDD is expected to continue its growth to become the second leading cause of disease burden (after HIV) by 2030. Despite an extensive research effort, the exact etiology of MDD remains elusive and the diagnostics uncertain. Moreover, a marked inter-individual variability is observed in the vulnerability to develop depression, as well as in response to antidepressant treatment, for nearly 50% of patients. Although a genetic component accounts for some cases of MDD, it is now clearly established that MDD results from strong gene and environment interactions. Such interactions could be mediated by epigenetic mechanisms, defined as chromatin and DNA modifications that alter gene expression without changing the DNA structure itself. Some epigenetic mechanisms have recently emerged as particularly relevant molecular substrates, promoting vulnerability or resilience to the development of depressive-like symptoms. Although the role of brainderived neurotrophic factor (BDNF) in the pathophysiology of MDD remains unclear, its modulation of the efficacy of antidepressants is clearly established. Therefore, in this review, we focus on the epigenetic mechanisms regulating the expression of BDNF in humans and in animal models of depression, and discuss their role in individual differences in vulnerability to depression and response to antidepressant drugs. KEY WORDS: BDNF, Epigenetics, Individual differences IntroductionMajor depressive disorder (MDD) is a common debilitating disorder (Bromet et al., 2011) affecting many aspects of the patient's life and family. In addition to its high comorbidity with other neuropsychiatric conditions and increased rate of suicide, depression has a variety of socioeconomic consequences, including low education, unstable employment, reduced work performance and marital dysfunction (Kessler and Bromet, 2013). In 2000, the economic costs of depression in the United States alone were estimated at $83.1 billion, encompassing direct medical costs, suicide-related mortality costs, as well as indirect workplace costs (Greenberg et al., 2003). Moreover, the prevalence of depressive disorders is expected to continue its growth and become by the year 2030 the second leading cause of disease burden among the World Health Organization member states (Mathers and Loncar, 2006). Despite extensive research efforts in past decades, the etiology of REVIEW Department of Biomedical Sciences, Neuroscience Program, Florida State University, Tallahassee, FL 32306, USA.*Author for correspondence (mohamed.kabbaj@med.fsu.edu) depression remains elusive, its diagnosis uncertain and the pharmacotherapy inefficient. Indeed, the antidepressants currently used, which target the monoaminergic pathways, require weeks to months of treatment and exhibit very poor or no response in nearly 50% of patients (Magni et al., 2013;Trivedi et al., 2006;Warden et al., 20...

show abstract

Lack of promoter IV‐driven BDNF transcription results in depression‐like behavior

Abstract: These results suggest that promoter IV-dependent BDNF expression plays a critical role in the control of moodrelated behaviors. This is the first study that directly addressed the effects of endogenous promoter-driven expression of BDNF in depression-like behavior.

Cited by 81 publications

References 55 publications

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

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

Role of activity-dependent BDNF expression in hippocampal–prefrontal cortical regulation of behavioral perseverance

Epigenetic mechanisms underlying the role of brain-derived neurotrophic factor in depression and response to antidepressants

Contact Info

Product

Resources

About