Selective Depletion of CREB in Serotonergic Neurons Affects the Upregulation of Brain-Derived Neurotrophic Factor Evoked by Chronic Fluoxetine Treatment.

Katarzyna Rafa-Zabłocka,Irena Nalepa,Grzegorz Kreiner,Monika Bagińska

doi:10.3389/fnins.2018.00637

Katarzyna Rafa-Zabłocka, Irena Nalepa + Show 2 more

Open Access

https://doi.org/10.3389/fnins.2018.00637

Copy DOI

Abstract

Neurotrophic factors are regarded as crucial regulatory components in neuronal plasticity and are postulated to play an important role in depression pathology. The abundant expression of brain-derived neurotrophic factor (BDNF) in various brain structures seems to be of particular interest in this context, as downregulation of BDNF is postulated to be correlated with depression and its upregulation is often observed after chronic treatment with common antidepressants. It is well-known that BDNF expression is regulated by cyclic AMP response element-binding protein (CREB). In our previous study using mice lacking CREB in serotonergic neurons (Creb1TPH2CreERT2 mice), we showed that selective CREB ablation in these particular neuronal populations is crucial for drug-resistant phenotypes in the tail suspension test observed after fluoxetine administration in Creb1TPH2CreERT2 mice. The aim of this study was to investigate the molecular changes in the expression of neurotrophins in Creb1TPH2CreERT2 mice after chronic fluoxetine treatment, restricted to the brain structures implicated in depression pathology with profound serotonergic innervation including the prefrontal cortex (PFC) and hippocampus. Here, we show for the first time that BDNF upregulation observed after fluoxetine in the hippocampus or PFC might be dependent on the transcription factor CREB residing, not within these particular structures targeted by serotonergic projections, but exclusively in serotonergic neurons. This observation may shed new light on the neurotrophic hypothesis of depression, where the effects of BDNF observed after antidepressants in the hippocampus and other brain structures were rather thought to be regulated by CREB residing within the same brain structures. Overall, these results provide further evidence for the pivotal role of CREB in serotonergic neurons in maintaining mechanisms of antidepressant drug action by regulation of BDNF levels.

Highlights

The majority of the current antidepressant therapies are based on the enhancement of monoaminergic transmission observed directly after drug administration, yet alleviation of depressive symptoms occur several weeks later
To determine whether the mutation impacted the effects of fluoxetine administration on neurotrophic factors, we screened the mRNA expression of Creb1, Bdnf, Ntf3, and Ngf as well as of the receptors of Bdnf and Ntf3, Ntrk2 (TrkB), and Ntrk3 (TrkC), respectively
We show for the first time that brain-derived neurotrophic factor (BDNF) upregulation in the hippocampus or prefrontal cortex (PFC) observed after antidepressants targeting the serotonergic system might be dependent on the transcription factor cyclic AMP response element-binding protein (CREB) residing not within these particular structures that are targeted by serotonergic projections, but exclusively in serotonergic neurons

Summary

Introduction

The majority of the current antidepressant therapies are based on the enhancement of monoaminergic transmission observed directly after drug administration, yet alleviation of depressive symptoms occur several weeks later. The abundant expression of brain-derived neurotrophic factor (BDNF) in various brain structures seems to be of particular relevance in this context. It is well-known that BDNF contributes to mechanisms of learning and memory by modulation of synaptic transmission and plasticity (Huang et al, 1999). Patients with depression are often associated with memory impairments, in particular regarding positive events, while memory for negative ones is potentiated (Dillon and Pizzagalli, 2018). According to the cognitive model of depression proposed by Beck, patients with major depressive disorder (MDD) are characterized by impaired cognitive processes, such as attention and memory, experiencing biased processing, rumination with dysfunctional attitudes and negative schemes (Disner et al, 2011). Alterations in BDNF levels may straightforwardly influence activity-dependent plasticity in the hippocampus, having direct impact on memory and emotions in patients with MDD (Phillips, 2017)

Objectives

Methods

Results

Conclusion