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.

The role of serotonin in adult hippocampal neurogenesis

“…Although survival and differentiation of newborn neurons were not affected, increased numbers of proliferating cells have been observed in the CA3 region of mouse hippocampus (Karabeg et al, 2013), whereas adult rat deficient in SERT showed increased numbers of immature neurons expressing DCX in the DG (Schipper et al, 2011). SERT knockdown by siRNA in adulthood also contributes to antidepressant action (Ferres-Coy et al, 2013).…”

Paradoxical effects of exercise on hippocampal plasticity and cognition in mice with a heterozygous null mutation in the serotonin transporter gene

“…To our knowledge, this is the first study assessing SERT HET mice reversal learning using the MWM. Indeed, previous investigation of SERT mutant mice using the MWM focused on the spatial learning phase only and found no differences between WT and SERT HET mice (Karabeg et al, ). This is consistent with our acquisition of allocentric search strategies data, which also revealed no genotype effect.…”

“…This is consistent with our acquisition of allocentric search strategies data, which also revealed no genotype effect. Interestingly, Karabeg et al () revealed that learning performance in the MWM was only altered after complete ablation of SERT (i.e., in the SERT homozygous KO mice). However, it is worth noting that the SERT homozygous KO mice were described in this study to have “stopped swimming,” which would have confounded clear interpretation on any learning performances.…”

“…This is consistent with our acquisition of allocentric search strategies data, which also revealed no genotype effect. Interestingly, Karabeg et al (2013) Brigman et al, 2010;Ineichen et al, 2012), the fact that exercised SERT HET mice no longer displayed intact spatial memory on the MWM reversal learning probe was unexpected. As chronic voluntary exercise is known to increase the circadian peak of plasma corticosterone and modulate stress response in mice (Otawa, Arai, & Atomi, 2007), it is quite plausible that SERT HET mice may respond differently to exercise, especially when combined with the acute stress component of swimming in the MWM.…”

Amygdala stimulation ameliorates memory impairments and promotes c‐Fos activity in fimbria‐fornix‐lesioned rats

“…We have followed the method described by (Karabeg et al, 2013). The rats of the different experimental groups were perfused under narcosis with formaldehyde 10%, the brain was removed and divided to the half transversally and kept in the same fixation solution during 48 hr at room temperature.…”