title: Roles of the serotonin 5-HT4 receptor in dendrite formation of the rat hippocampal neurons in vitro.
abstract: Serotonin (5-HT) is involved in various aspects of hippocampal development, although the specific roles of 5-HT receptors are poorly understood. We investigated the roles of 5-HT receptors in the dendrite formation of hippocampal neurons. We focused on the 5-HT4 receptor, which is coupled with Gs protein, and compared the effects with those of the Gi-coupled 5-HT1A receptor. Neurons from rat hippocampi at embryonic day 18 were dissociated and treated for 4 days with the 5-HT4 receptor agonist BIMU8 or the 5-HT1A receptor agonist 8-OH DPAT. The formation of primary dendrites and dendrite branching were promoted by BIMU8, whereas the dendrite branching was inhibited by 8-OH DPAT. BIMU8-induced promotion of dendrite formation was neutralized by concomitant treatment with the 5-HT4 receptor antagonist, confirming the specific actions of the 5-HT4 receptor. We then examined the signaling mechanisms underlying the actions of the 5-HT4 receptor by using a protein kinase A (PKA) inhibitor. The BIMU8-induced promotion of dendrite formation was reversed partially by the PKA inhibitor, suggesting involvement of PKA signaling downstream of the 5-HT4 receptor. Finally, we examined the contribution of brain-derived neurotrophic factor (BDNF) to the promotion of dendrite formation by BIMU8. Quantitative RT-PCR analysis showed that BIMU8 increased the BDNF mRNA expression and that treatment of cultured neurons with the TrkB antagonist reversed the BIMU8-induced increase in dendrite formation. In summary, the present study suggests a novel role for the 5-HT4 receptor in facilitation of dendrite formation in which intracellular signaling of PKA and the BDNF-TrkB system may be involved.
authors.affiliation: University of Tsukuba, Graduate School of Comprehensive Human Sciences, 1-1-1 Tennodai, Tsukuba 305-8577, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Kozono
authors.affiliation: University of Tsukuba, Graduate School of Comprehensive Human Sciences, 1-1-1 Tennodai, Tsukuba 305-8577, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Ohtani
authors.affiliation: University of Tsukuba, Graduate School of Comprehensive Human Sciences, 1-1-1 Tennodai, Tsukuba 305-8577, Japan; Department of Neurobiology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8577, Japan. Electronic address: tshiga@md.tsukuba.ac.jp.
authors.forename: Takashi
authors.initials: T
authors.lastname: Shiga
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003712:Dendrites / Q000187:drug effects / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D007150:Immunohistochemistry; D000071446:Neuronal Outgrowth / Q000187:drug effects / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D017208:Rats, Wistar; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism; D020813:Receptor, trkB / Q000037:antagonists & inhibitors / Q000378:metabolism; D044422:Receptors, Serotonin, 5-HT4 / Q000378:metabolism*; D058825:Serotonin 5-HT1 Receptor Agonists / Q000494:pharmacology; D058828:Serotonin 5-HT4 Receptor Agonists / Q000494:pharmacology; D058832:Serotonin 5-HT4 Receptor Antagonists / Q000494:pharmacology
chemical_list: D001562:Benzimidazoles; D019208:Brain-Derived Neurotrophic Factor; D019086:Bridged Bicyclo Compounds, Heterocyclic; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D058825:Serotonin 5-HT1 Receptor Agonists; D058828:Serotonin 5-HT4 Receptor Agonists; D058832:Serotonin 5-HT4 Receptor Antagonists; D044282:Receptor, Serotonin, 5-HT1A; C070189:(endo-N-8-methyl-8-azabicyclo-(3.2.1)oct-3-yl)-2,3-dihydro-3-isopropyl-2-oxo-1H-benzimidazol-1-carboxamide; D044422:Receptors, Serotonin, 5-HT4; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D020813:Receptor, trkB; D017868:Cyclic AMP-Dependent Protein Kinases
keywords: Dendrite formation; Dissociated cell culture; Hippocampus; Serotonin; Serotonin 4 receptor