CREB-mediated synaptogenesis and neurogenesis is crucial for the role of 5-HT1a receptors in modulating anxiety behaviors

• Published in: Scientific reports 2016-07, Vol.6 (1), p.29551-29551, Article 29551
• Main Authors: Zhang, Jing, Cai, Cheng-Yun, Wu, Hai-Yin, Zhu, Li-Juan, Luo, Chun-Xia, Zhu, Dong-Ya
• Format: Article
• Language: English
• Subjects: 13/1; 14/1; 14/32; 14/63; 42/89; 631/378/1689/1300; 631/378/2591; 64/60; Animals; Anxiety; Anxiety - metabolism; Cyclic AMP Response Element-Binding Protein - metabolism; Dendrites; Dendrites - pathology; Hippocampus - metabolism; Hippocampus - pathology; Humanities and Social Sciences; Irradiation; Male; Mice, Inbred ICR; multidisciplinary; Neurogenesis; Receptor, Serotonin, 5-HT1A - metabolism; Science; Spine; Synapses - metabolism
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep29551

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.