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.
Intracellular 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.
School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.
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L
Zhou
Department of Psychiatry, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China.
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SL
Ma
School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.|State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.
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PK
Yeung
Division of Life Science and the Biotechnology Research Institute, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong SAR, China.|State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong SAR, China.
Y H
YH
Wong
State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong SAR, China.|Division of Life Science and Center for Chinese Medicine, Hong Kong University of Science and Technology, Clear Water Bay, Clear Water Bay, Hong Kong SAR, China.
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KW
Tsim
School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.|Research Center of Heart, Brain, Hormone and Healthy Aging, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.|State Key Laboratory of Brain and Cognitive Science, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.|Department of Ophthalmology, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.
K F
KF
So
Department of Psychiatry, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China.
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LC
Lam
School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.|State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.|Research Center of Heart, Brain, Hormone and Healthy Aging, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.
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SK
Chung
D000339:Affect / Q000187:drug effects; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics*; D000818:Animals; D001007:Anxiety / Q000235:genetics*; D044466:Asian People / Q000235:genetics; D001522:Behavior, Animal / Q000187:drug effects; D000242:Cyclic AMP; D003863:Depression / Q000235:genetics*; D005260:Female; D005473:Fluoxetine / Q000494:pharmacology; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics*; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D006801:Humans; D008297:Male; D018345:Mice, Knockout; D055495:Neurogenesis / Q000235:genetics; D012149:Restraint, Physical; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D013315:Stress, Psychological; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D000242:Cyclic AMP; D005473:Fluoxetine; D020662:Guanine Nucleotide Exchange Factors; D017367:Selective Serotonin Reuptake Inhibitors; D005680:gamma-Aminobutyric Acid; C482601:Epac protein, mouse; C116122:RAPGEF3 protein, human; C442864:RAPGEF4 protein, human; C486707:Rapgef4 protein, mouse