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Constitutive Activity of Serotonin Receptor 6 Regulates Human Cerebral Organoids Formation and Depression-like Behaviors.


ABSTRACT: Serotonin receptor 6 (5-HT6R), a typical G protein-coupled receptor (GPCR) mainly expressed in the neurogenic area with constitutive activity, is of particular interest as a promising target for emotional impairment. Here, we found that 5-HT6R was highly expressed in human NSCs and activation of the receptor promoted self-renewal of human NSCs, and thus induced the expansion and folding of human cerebral organoids; dysfunction of receptor or inhibition of its constitutive activity resulted in the premature differentiation of NSCs, which ultimately depleted the NSC pool. The following mechanistic study revealed that EPAC-CREB signaling was involved in 5-HT6R regulation. Furthermore, we showed that mice with genetic deletion of 5-HT6R or knockin A268R mutant presented depression-like behaviors and impaired hippocampal neurogenesis for progressive decrease of the NSC pool. Thus, this study indicates that the modulation of 5-HT6R and its constitutive activity may provide a therapeutic alternative to alleviate depression.

SUBMITTER: Wang Q 

PROVIDER: S-EPMC7815944 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Constitutive Activity of Serotonin Receptor 6 Regulates Human Cerebral Organoids Formation and Depression-like Behaviors.

Wang Qinying Q   Dong Xiaoxu X   Hu Tingting T   Qu Chao C   Lu Jing J   Zhou Yue Y   Li Jinsong J   Pei Gang G  

Stem cell reports 20201223 1


Serotonin receptor 6 (5-HT<sub>6</sub>R), a typical G protein-coupled receptor (GPCR) mainly expressed in the neurogenic area with constitutive activity, is of particular interest as a promising target for emotional impairment. Here, we found that 5-HT<sub>6</sub>R was highly expressed in human NSCs and activation of the receptor promoted self-renewal of human NSCs, and thus induced the expansion and folding of human cerebral organoids; dysfunction of receptor or inhibition of its constitutive a  ...[more]

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