TY  - JOUR
A1  - Wolf, Karen
A1  - Braun, Attila
A1  - Haining, Elizabeth J.
A1  - Tseng, Yu-Lun
A1  - Kraft, Peter
A1  - Schuhmann, Michael K.
A1  - Gotru, Sanjeev K.
A1  - Chen, Wenchun
A1  - Hermanns, Heike M.
A1  - Stoll, Guido
A1  - Lesch, Klaus-Peter
A1  - Nieswandt, Bernhard
T1  - Partially Defective Store Operated Calcium Entry and Hem(ITAM) Signaling in Platelets of Serotonin Transporter Deficient Mice
JF  - PLoS One
N2  - Background
Serotonin (5-hydroxytryptamin, 5-HT) is an indolamine platelet agonist, biochemically derived from tryptophan. 5-HT is secreted from the enterochromaffin cells into the gastrointestinal tract and blood. Blood 5-HT has been proposed to regulate hemostasis by acting as a vasoconstrictor and by triggering platelet signaling through 5-HT receptor 2A (5HTR2A). Although platelets do not synthetize 5-HT, they take 5-HT up from the blood and store it in their dense granules which are secreted upon platelet activation.

Objective
To identify the molecular composite of the 5-HT uptake system in platelets and elucidate the role of platelet released 5-HT in thrombosis and ischemic stroke. Methods: 5-HT transporter knockout mice (5Htt\(^{-/-}\)) were analyzed in different in vitro and in vivo assays and in a model of ischemic stroke.

Results
In 5Htt\(^{-/-}\) platelets, 5-HT uptake from the blood was completely abolished and agonist-induced Ca2+ influx through store operated Ca\(^{2+}\) entry (SOCE), integrin activation, degranulation and aggregation responses to glycoprotein VI (GPVI) and C-type lectin-like receptor 2 (CLEC-2) were reduced. These observed in vitro defects in 5Htt\(^{-/-}\) platelets could be normalized by the addition of exogenous 5-HT. Moreover, reduced 5-HT levels in the plasma, an increased bleeding time and the formation of unstable thrombi were observed ex vivo under flow and in vivo in the abdominal aorta and carotid artery of 5Htt\(^{-/-}\) mice. Surprisingly, in the transient middle cerebral artery occlusion (tMCAO) model of ischemic stroke 5Htt\(^{-/-}\) mice showed nearly normal infarct volume and the neurological outcome was comparable to control mice.

Conclusion
Although secreted platelet 5-HT does not appear to play a crucial role in the development of reperfusion injury after stroke, it is essential to amplify the second phase of platelet activation through SOCE and plays an important role in thrombus stabilization.
KW  - platelets
KW  - serotonin
KW  - integrins
KW  - blood flow
KW  - collagens
KW  - platelet activation
KW  - platelet aggregation
KW  - ischemic stroke
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-146399
VL  - 11
IS  - 1
ER  - 
TY  - JOUR
A1  - Song, Ning-Ning
A1  - Jia, Yun-Fang
A1  - Zhang, Lei
A1  - Zhang, Qiong
A1  - Huang, Ying
A1  - Liu, Xiao-Zhen
A1  - Hu, Ling
A1  - Lan, Wei
A1  - Chen, Ling
A1  - Lesch, Klaus-Peter
A1  - Chen, Xiaoyan
A1  - Xu, Lin
A1  - Ding, Yu-Qiang
T1  - Reducing central serotonin in adulthood promotes hippocampal neurogenesis
JF  - Scientific Reports
N2  - Chronic administration of selective serotonin reuptake inhibitors (SSRIs), which up-regulates central serotonin (5-HT) system function, enhances adult hippocampal neurogenesis. However, the relationship between central 5-HT system and adult neurogenesis has not fully been understood. Here, we report that lowering 5-HT level in adulthood is also able to enhance adult hippocampal neurogenesis. We used tamoxifen (TM)-induced Cre in Pet1-CreER\(^{T2}\) mice to either deplete central serotonergic (5-HTergic) neurons or inactivate 5-HT synthesis in adulthood and explore the role of central 5-HT in adult hippocampal neurogenesis. A dramatic increase in hippocampal neurogenesis is present in these two central 5-HT-deficient mice and it is largely prevented by administration of agonist for 5-HTR2c receptor. In addition, the survival of new-born neurons in the hippocampus is enhanced. Furthermore, the adult 5-HT-deficient mice showed reduced depression-like behaviors but enhanced contextual fear memory. These findings demonstrate that lowering central 5-HT function in adulthood can also enhance adult hippocampal neurogenesis, thus revealing a new aspect of central 5-HT in regulating adult neurogenesis.
KW  - serotonin
KW  - SSRI
KW  - hippocampal neurogenesis
KW  - adulthood
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-168004
VL  - 6
IS  - 20338
ER  -