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Article: Anxiety and depression with neurogenesis defects in exchange protein directly activated by cAMP 2-deficient mice are ameliorated by a selective serotonin reuptake inhibitor, Prozac

TitleAnxiety and depression with neurogenesis defects in exchange protein directly activated by cAMP 2-deficient mice are ameliorated by a selective serotonin reuptake inhibitor, Prozac
Authors
Issue Date2016
PublisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/tp/index.html
Citation
Translational Psychiatry, 2016, v. 6, p. article no. e881 How to Cite?
AbstractIntracellular cAMP and serotonin are important modulators of anxiety and depression. Fluoxetine, a selective serotonin reuptake inhibitor (SSRI) also known as Prozac, is widely used against depression, potentially by activating cAMP response element-binding protein (CREB) and increasing brain-derived neurotrophic factor (BDNF) through protein kinase A (PKA). However, the role of Epac1 and Epac2 (Rap guanine nucleotide exchange factors, RAPGEF3 and RAPGEF4, respectively) as potential downstream targets of SSRI/cAMP in mood regulations is not yet clear. Here, we investigated the phenotypes of Epac1 (Epac1− / −) or Epac2 (Epac2− / −) knockout mice by comparing them with their wild-type counterparts. Surprisingly, Epac2− / − mice exhibited a wide range of mood disorders, including anxiety and depression with learning and memory deficits in contextual and cued fear-conditioning tests without affecting Epac1 expression or PKA activity. Interestingly, rs17746510, one of the three single-nucleotide polymorphisms (SNPs) in RAPGEF4 associated with cognitive decline in Chinese Alzheimer’s disease (AD) patients, was significantly correlated with apathy and mood disturbance, whereas no significant association was observed between RAPGEF3 SNPs and the risk of AD or neuropsychiatric inventory scores. To further determine the detailed role of Epac2 in SSRI/serotonin/cAMP-involved mood disorders, we treated Epac2− / − mice with a SSRI, Prozac. The alteration in open field behavior and impaired hippocampal cell proliferation in Epac2− / − mice were alleviated by Prozac. Taken together, Epac2 gene polymorphism is a putative risk factor for mood disorders in AD patients in part by affecting the hippocampal neurogenesis.
Persistent Identifierhttp://hdl.handle.net/10722/228672
ISSN
2015 Impact Factor: 5.538
2015 SCImago Journal Rankings: 3.057

 

DC FieldValueLanguage
dc.contributor.authorZhou, L-
dc.contributor.authorMa, SL-
dc.contributor.authorYeung, PKK-
dc.contributor.authorWong, YH-
dc.contributor.authorTsim, KWK-
dc.contributor.authorLam, LCW-
dc.contributor.authorChung, SK-
dc.date.accessioned2016-08-23T14:06:22Z-
dc.date.available2016-08-23T14:06:22Z-
dc.date.issued2016-
dc.identifier.citationTranslational Psychiatry, 2016, v. 6, p. article no. e881-
dc.identifier.issn2158-3188-
dc.identifier.urihttp://hdl.handle.net/10722/228672-
dc.description.abstractIntracellular cAMP and serotonin are important modulators of anxiety and depression. Fluoxetine, a selective serotonin reuptake inhibitor (SSRI) also known as Prozac, is widely used against depression, potentially by activating cAMP response element-binding protein (CREB) and increasing brain-derived neurotrophic factor (BDNF) through protein kinase A (PKA). However, the role of Epac1 and Epac2 (Rap guanine nucleotide exchange factors, RAPGEF3 and RAPGEF4, respectively) as potential downstream targets of SSRI/cAMP in mood regulations is not yet clear. Here, we investigated the phenotypes of Epac1 (Epac1− / −) or Epac2 (Epac2− / −) knockout mice by comparing them with their wild-type counterparts. Surprisingly, Epac2− / − mice exhibited a wide range of mood disorders, including anxiety and depression with learning and memory deficits in contextual and cued fear-conditioning tests without affecting Epac1 expression or PKA activity. Interestingly, rs17746510, one of the three single-nucleotide polymorphisms (SNPs) in RAPGEF4 associated with cognitive decline in Chinese Alzheimer’s disease (AD) patients, was significantly correlated with apathy and mood disturbance, whereas no significant association was observed between RAPGEF3 SNPs and the risk of AD or neuropsychiatric inventory scores. To further determine the detailed role of Epac2 in SSRI/serotonin/cAMP-involved mood disorders, we treated Epac2− / − mice with a SSRI, Prozac. The alteration in open field behavior and impaired hippocampal cell proliferation in Epac2− / − mice were alleviated by Prozac. Taken together, Epac2 gene polymorphism is a putative risk factor for mood disorders in AD patients in part by affecting the hippocampal neurogenesis.-
dc.languageeng-
dc.publisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/tp/index.html-
dc.relation.ispartofTranslational Psychiatry-
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.titleAnxiety and depression with neurogenesis defects in exchange protein directly activated by cAMP 2-deficient mice are ameliorated by a selective serotonin reuptake inhibitor, Prozac-
dc.typeArticle-
dc.identifier.emailZhou, L: lenazhou@hku.hk-
dc.identifier.emailYeung, PKK: ykkp@hkucc.hku.hk-
dc.identifier.emailChung, SK: skchung@hkucc.hku.hk-
dc.identifier.authorityChung, SK=rp00381-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1038/tp.2016.129-
dc.identifier.hkuros260394-
dc.identifier.volume6-
dc.identifier.spagearticle no. e881-
dc.identifier.epagearticle no. e881-
dc.publisher.placeUnited Kingdom-

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