The Antidepressant Fluoxetine Mobilizes Vesicles to the Recycling Pool of Rat Hippocampal Synapses During High Activity

Jung, Jasmin; Loy, Kristina; Schilling, Eva-Maria; Röther, Mareike; Brauner, Jan Markus; Huth, Tobias; Schlötzer‐Schrehardt, Ursula; Alzheimer, Christian; Kornhuber, Johannes; Welzel, Oliver; Groemer, Teja W.

doi:10.1007/s12035-013-8569-5

Cited by 10 publications

(9 citation statements)

References 90 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In order to test whether these changes were related to pathological intra-synaptic mechanisms, fluoxetine was applied between the first and the second stimulation cycles. Fluoxetine, a classical SSRI-class anti-depression drug, was found to reduce excitotoxicity and to increase the mobilization of synaptic vesicles (Kim et al, 2013; Jung et al, 2014). Application of fluoxetine reversed and even over-compensated these kinetic changes.…”

Section: Resultsmentioning

confidence: 99%

“…Application of fluoxetine significantly stabilized the release mode, reduced the proportion of delayed synapses, and increased fast and bi-phasic synapses. This effect could be due to the increased size of the synaptic vesicle recycling pool and increased facilitation of exocytosis by fluoxetine (Jung et al, 2014). If our assumption was correct that delayed FM1-43 release onset was caused by the transient opening of a fusion pore that preceded the full fusion event, we could speculate that increased availability of vesicles for release shortened this pore transition toward full collapse.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Differential Release of Exocytosis Marker Dyes Indicates Stimulation-Dependent Regulation of Synaptic Activity

2019

Self Cite

View full text Add to dashboard Cite

There is a general consensus that synaptic vesicular release by a full collapse process is the primary machinery of synaptic transmission. However, competing view suggests that synaptic vesicular release operates via a kiss-and-run mechanism. By monitoring the release dynamics of a synaptic vesicular marker, FM1-43 from individual synapses in hippocampal neurons, we found evidence that the release of synaptic vesicle was delayed by several seconds after the start of field stimulation. This phenomenon was associated with modified opening kinetics of fusion pores. Detailed analysis revealed that some synapses were completely inactive for a few seconds after stimulation, despite immediate calcium influx. This delay in vesicular release was modulated by various stimulation protocols and different frequencies, indicating an activity-dependent regulation mechanism for neurotransmitter exocytosis. Staurosporine, a drug known to induce “kiss-and-run” exocytosis, increased the proportion of delayed synapses as well as the delay duration, while fluoxetine acted contrarily. Besides being a serotonin reuptake inhibitor, it directly enhanced vesicle mobilization and reduced synaptic fatigue. Exocytosis was never delayed, when it was monitored with pH-sensitive probes, synaptopHlourin and αSyt-CypHerE5 antibody, indicating an instantaneous formation of a fusion pore that allowed rapid equilibration of vesicular lumenal pH but prevented FM1-43 release because of its slow dissociation from the inner vesicular membrane. Our observations suggest that synapses operate via a sequential “kiss-and-run” and “full-collapse” exocytosis mechanism. The initially narrow vesicular pore allows the equilibration of intravesicular pH which then progresses toward full fusion, causing FM1-43 release.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Differential Release of Exocytosis Marker Dyes Indicates Stimulation-Dependent Regulation of Synaptic Activity

2019

Self Cite

View full text Add to dashboard Cite

show abstract

“…The relative size of the different released vesicle pools was calculated from the stepwise increase of synaptic fluorescence upon stimulation and its linear proportionality to the relative number of released vesicles. 50 …”

Section: Methodsmentioning

confidence: 99%

“… 45 , 46 , 47 , 48 Major depressive disorder—one of the common adverse effects of glioblastoma treatment 49 —has been related to a vesicle pool size pathology. 50 Quantifying the vesicle pool sizes of neurons treated with sorafenib and erastin therefore is a valuable addition to the common approaches on drug safety.…”

Section: Introductionmentioning

confidence: 99%

Chemotherapeutic xCT inhibitors sorafenib and erastin unraveled with the synaptic optogenetic function analysis tool

et al. 2017

View full text Add to dashboard Cite

In the search for new potential chemotherapeutics, the compounds’ toxicity to healthy cells is an important factor. The brain with its functional units, the neurons, is especially endangered during the radio- and chemotherapeutic treatment of brain tumors. The effect of the potential compounds not only on neuronal survival but also neuronal function needs to be taken into account. Therefore, in this study we aimed to comprehend the biological effects of chemotherapeutic xCT inhibition on healthy neuronal cells with our synaptic optogenetic function analysis tool (SOFA). We combined common approaches, such as investigation of morphological markers, neuronal function and cell metabolism. The glutamate-cystine exchanger xCT (SLC7A11, system Xc−) is the main glutamate exporter in malignant brain tumors and as such a relevant drug target for treating deadly glioblastomas (WHO grades III and IV). Recently, two small molecules termed sorafenib (Nexavar) and erastin have been found to efficiently block xCT function. We investigated neuronal morphology, metabolic secretome profiles, synaptic function and cell metabolism of primary hippocampal cultures (containing neurons and glial cells) treated with sorafenib and erastin in clinically relevant concentrations. We found that sorafenib severely damaged neurons already after 24 h of treatment. Noteworthy, also at a lower concentration, where no morphological damage or metabolic disturbance was monitored, sorafenib still interfered with synaptic and metabolic homeostasis. In contrast, erastin-treated neurons displayed mostly inconspicuous morphology and metabolic rates. Key parameters of proper neuronal function, such as synaptic vesicle pool sizes, were however disrupted following erastin application. In conclusion, our data revealed that while sorafenib and erastin effectively inhibited xCT function they also interfered with essential neuronal (synaptic) function. These findings highlight the particular importance of investigating the effects of potential neurooncological and general cancer chemotherapeutics also on healthy neuronal cells and their function as revealed by the SOFA tool.

show abstract

“…Fluoxetine can increase the occurrence of hippocampal neurons in rats with depression, improve the stereology of synaptic structures, and restore the structure and function of the hippocampus [26]. Fluoxetine can reduce the expression of Bax mRNA in the hippocampus of rats with depression, increase the expression of Bcl-2 mRNA, and reduce neuronal apoptosis [27].…”

Section: Introductionmentioning

confidence: 99%

Antidepressant-Like Effects and Cognitive Enhancement of Coadministration of Chaihu Shugan San and Fluoxetine: Dependent on the BDNF-ERK-CREB Signaling Pathway in the Hippocampus and Frontal Cortex

Yan

et al. 2020

BioMed Research International

View full text Add to dashboard Cite

Background. Fluoxetine (FLU) is the first-line and widely used medication for depression; however, FLU treatment is almost ineffective in 30%-40% of patients with depression. In addition, there are some problems in FLU treatment, such as delayed efficacy, large side effects, and poor tolerance. Chaihu Shugan San (CSS) is a classic and effective antidepressant Chinese herbal medicine that has been used in China for thousands of years. CSS or coadministration of CSS and FLU has become one of the most recommended methods in the treatment of depression in China. However, the specific pathways of CSS and coadministration of CSS and FLU for antidepressant are still unclear. Objective. This study was designed to evaluate the antidepressant effects of CSS and coadministration of CSS and FLU. Methods. The chronic unpredictable mild stress (CUMS) rat model was used to simulate depression. 120 healthy adult male Sprague-Dawley (SD) rats were randomly divided into seven groups: the control group, CUMS group, low-dose CSS group, high-dose CSS group, FLU group, coadministration of low-dose CSS and FLU group, and coadministration of high-dose CSS and FLU group. The rats in different groups were given different interventions. Then, the depression-like behavior and cognitive function were evaluated by the sucrose preference test (SPT), forced swimming test (FST), open field test (OFT), and Y-maze test. What is more, the antidepressant mechanism of CSS and coadministration of CSS and FLU were studied through BDNF mRNA, ERK mRNA, CREB mRNA, BDNF, p-ERK/ERK, and p-CREB/CREB levels in the hippocampus and frontal cortex by Western blot and RT-PCR. Results. Compared with the CUMS group, CSS and coadministration of CSS and FLU could alleviate the depressive symptoms and improve cognitive function in CUMS rats (p<0.05); CSS and coadministration of CSS and FLU could increase the expression of BDNF, p-CREB/CREB, p-ERK/ERK, and BDNF mRNA, CREB mRNA, and ERK mRNA in the hippocampus and frontal cortex (p<0.05). Besides, the high-dose CSS combined with the fluoxetine group was significantly better than the fluoxetine group and CSS group (p<0.05). Discussion and Conclusion. Finally, we found that both CSS and coadministration of CSS and FLU play an antidepressant role, which may be due to the regulation of the BDNF/ERK/CREB signaling pathway in the hippocampus and frontal cortex. Among them, the coadministration of CSS and FLU can enhance the antidepressant effect of CSS or FLU alone, and the underlying mechanism needs further investigation.

show abstract

The Antidepressant Fluoxetine Mobilizes Vesicles to the Recycling Pool of Rat Hippocampal Synapses During High Activity

Cited by 10 publications

References 90 publications

Differential Release of Exocytosis Marker Dyes Indicates Stimulation-Dependent Regulation of Synaptic Activity

Differential Release of Exocytosis Marker Dyes Indicates Stimulation-Dependent Regulation of Synaptic Activity

Chemotherapeutic xCT inhibitors sorafenib and erastin unraveled with the synaptic optogenetic function analysis tool

Antidepressant-Like Effects and Cognitive Enhancement of Coadministration of Chaihu Shugan San and Fluoxetine: Dependent on the BDNF-ERK-CREB Signaling Pathway in the Hippocampus and Frontal Cortex

Contact Info

Product

Resources

About