title: Serotonin 1A auto-receptors are not sufficient to modulate anxiety in mice.
abstract: The neurotransmitter serotonin plays an important role in modulating diverse behavioral traits. Mice lacking the serotonin 1A receptor (Htr1a) show elevated avoidance of novel open spaces, suggesting that it has a role in modulating anxiety behavior. Htr1a is a Gαi -coupled G-protein-coupled receptor expressed on serotonin neurons (auto-receptor), where it mediates negative feedback of serotonin neuron firing. Htr1a is also expressed on non-serotonin neurons (hetero-receptor) in diverse brain regions, where it mediates an inhibitory effect of serotonin on neuronal activity. Debate exists about which of these receptor populations is responsible for the modulatory effects of Htr1a on anxiety. Studies using tissue-specific transgenic expression have suggested that forebrain Htr1a hetero-receptors are sufficient to restore normal anxiety behavior to Htr1a knockout mice. At the same time, experiments using tissue-specific transgenic suppression of Htr1a expression have demonstrated that Htr1a auto-receptors, but not forebrain hetero-receptors, are necessary for normal anxiety behavior. One interpretation of these data is that multiple Htr1a receptor populations are involved in modulating anxiety. Here, we aimed to test this hypothesis by determining whether Htr1a auto-receptors are sufficient to restore normal anxiety to Htr1a knockout animals. Transgenic mice expressing Htr1a under the control of the tryptophan hydroxylase 2 (Tph2) promoter showed restored Htr1a-mediated serotonin negative feedback and hypothermia, but anxiety behavior indistinguishable from that of knockout mice. These data show that, in the absence of Htr1a hetero-receptors, auto-receptors are unable to have an impact on anxiety. When combined with previous data, these findings support the hypothesis that Htr1a auto-receptors are necessary, but not sufficient, to modulate anxiety.
authors.affiliation: Mouse Biology Unit, European Molecular Biology Laboratory (EMBL), Monterotondo, Italy.
authors.forename: Lukasz
authors.initials: L
authors.lastname: Piszczek
authors.forename: Kevin
authors.initials: K
authors.lastname: Schlax
authors.forename: Anna
authors.initials: A
authors.lastname: Wyrzykowska
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Piszczek
authors.forename: Enrica
authors.initials: E
authors.lastname: Audero
authors.forename: Cornelius
authors.initials: C
authors.lastname: Thilo Gross
mesh_terms: D000818:Animals; D001007:Anxiety / Q000503:physiopathology*; D017660:Autoreceptors / Q000378:metabolism; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D044282:Receptor, Serotonin, 5-HT1A / Q000235:genetics / Q000378:metabolism*
chemical_list: D017660:Autoreceptors; D044282:Receptor, Serotonin, 5-HT1A
keywords: anxiety; serotonin; serotonin 1A receptor; transgenic mice