title: 5-HTT deficiency affects neuroplasticity and increases stress sensitivity resulting in altered spatial learning performance in the Morris water maze but not in the Barnes maze.
abstract: The purpose of this study was to evaluate whether spatial hippocampus-dependent learning is affected by the serotonergic system and stress. Therefore, 5-HTT knockout (-/-), heterozygous (+/-) and wildtype (+/+) mice were subjected to the Barnes maze (BM) and the Morris water maze (WM), the latter being discussed as more aversive. Additionally, immediate early gene (IEG) expression, hippocampal adult neurogenesis (aN), and blood plasma corticosterone were analyzed. While the performance of 5-HTT-/- mice in the BM was undistinguishable from both other genotypes, they performed worse in the WM. However, in the course of the repeated WM trials 5-HTT-/- mice advanced to wildtype level. The experience of a single trial of either the WM or the BM resulted in increased plasma corticosterone levels in all genotypes. After several trials 5-HTT-/- mice exhibited higher corticosterone concentrations compared with both other genotypes in both tests. Corticosterone levels were highest in 5-HTT-/- mice tested in the WM indicating greater aversiveness of the WM and a greater stress sensitivity of 5-HTT deficient mice. Quantitative immunohistochemistry in the hippocampus revealed increased cell counts positive for the IEG products cFos and Arc as well as for proliferation marker Ki67 and immature neuron marker NeuroD in 5-HTT-/- mice compared to 5-HTT+/+ mice, irrespective of the test. Most differences were found in the suprapyramidal blade of the dentate gyrus of the septal hippocampus. Ki67-immunohistochemistry revealed a genotype x environment interaction with 5-HTT genotype differences in naïve controls and WM experience exclusively yielding more Ki67-positive cells in 5-HTT+/+ mice. Moreover, in 5-HTT-/- mice we demonstrate that learning performance correlates with the extent of aN. Overall, higher baseline IEG expression and increased an in the hippocampus of 5-HTT-/- mice together with increased stress sensitivity may constitute the neurobiological correlate of raised alertness, possibly impeding optimal learning performance in the more stressful WM.
authors.affiliation: Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Würzburg, Germany ; Division of Molecular Psychiatry, Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Würzburg, Germany.
authors.forename: Margherita M
authors.initials: MM
authors.lastname: Karabeg
authors.forename: Sandra
authors.initials: S
authors.lastname: Grauthoff
authors.forename: Sina Y
authors.initials: SY
authors.lastname: Kollert
authors.forename: Magdalena
authors.initials: M
authors.lastname: Weidner
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Heiming
authors.forename: Friederike
authors.initials: F
authors.lastname: Jansen
authors.forename: Sandy
authors.initials: S
authors.lastname: Popp
authors.forename: Sylvia
authors.initials: S
authors.lastname: Kaiser
authors.forename: Klaus-Peter
authors.initials: KP
authors.lastname: Lesch
authors.forename: Norbert
authors.initials: N
authors.lastname: Sachser
authors.forename: Angelika G
authors.initials: AG
authors.lastname: Schmitt
authors.forename: Lars
authors.initials: L
authors.lastname: Lewejohann
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis; D003345:Corticosterone / Q000097:blood; D005786:Gene Expression Regulation; D006624:Hippocampus / Q000378:metabolism*; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D018782:Maze Learning / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000096:biosynthesis; D009473:Neuronal Plasticity / Q000502:physiology*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D013312:Stress, Physiological / Q000502:physiology*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D003345:Corticosterone; D019394:Ki-67 Antigen; D009419:Nerve Tissue Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; C093564:Neurogenic differentiation factor 1