title: CREB-mediated synaptogenesis and neurogenesis is crucial for the role of 5-HT1a receptors in modulating anxiety behaviors.
abstract: Serotonin 1a-receptor (5-HT1aR) has been specifically implicated in the pathogenesis of anxiety. However, the mechanism underlying the role of 5-HT1aR in anxiety remains poorly understood. Here we show in mice that the transcription factor cAMP response element binding protein (CREB) in the hippocampus functions as an effector of 5-HT1aR in modulating anxiety-related behaviors. We generated recombinant lentivirus LV-CREB133-GFP expressing a dominant negative CREB which could not be phosphorylated at Ser133 to specifically reduce CREB activity, and LV-VP16-CREB-GFP expressing a constitutively active fusion protein VP16-CREB which could be phosphorylated by itself to specifically enhance CREB activity. LV-CREB133-GFP neutralized 5-HT1aR agonist-induced up-regulation of synapse density, spine density, dendrite complexity, neurogenesis, and the expression of synapsin and spinophilin, two well-characterized synaptic proteins, and abolished the anxiolytic effect of 5-HT1aR agonist; whereas LV-VP16-CREB-GFP rescued the 5-HT1aR antagonist-induced down-regulation of synapse density, spine density, dendrite complexity, neurogenesis and synapsin and spinophilin expression, and reversed the anxiogenic effect of 5-HT1aR antagonist. The deletion of neurogenesis by irradiation or the diminution of synaptogenesis by knockdown of synapsin expression abolished the anxiolytic effects of both CREB and 5-HT1aR activation. These findings suggest that CREB-mediated hippoacampus structural plasticity is crucial for the role of 5-HT1aR in modulating anxiety-related behaviors.
authors.affiliation: Department of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing 210029, China.|Institution of Stem Cells and Neuroregeneration, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Cheng-Yun
authors.initials: CY
authors.lastname: Cai
authors.affiliation: Department of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing 210029, China.|Institution of Stem Cells and Neuroregeneration, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Hai-Yin
authors.initials: HY
authors.lastname: Wu
authors.affiliation: Institute of Neuroscience, Soochow University, Su zhou, China.
authors.forename: Li-Juan
authors.initials: LJ
authors.lastname: Zhu
authors.affiliation: Department of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing 210029, China.|Institution of Stem Cells and Neuroregeneration, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Chun-Xia
authors.initials: CX
authors.lastname: Luo
authors.affiliation: Department of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing 210029, China.|Institution of Stem Cells and Neuroregeneration, Nanjing Medical University, Nanjing 210029, China.|The key laboratory of human functional genomics of Jiangsu Province, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Dong-Ya
authors.initials: DY
authors.lastname: Zhu
mesh_terms: D000818:Animals; D001007:Anxiety / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D003712:Dendrites / Q000473:pathology; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D008297:Male; D008813:Mice, Inbred ICR; D055495:Neurogenesis; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism*
chemical_list: C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D044282:Receptor, Serotonin, 5-HT1A