Karpova Nina N, Lindholm Jesse Saku Olavi, Kulesskaya Natalia, Onishchenko Natalia, Vahter Marie, Popova Dina, Ceccatelli Sandra, Castrén Eero
Neuroscience Center, University of Helsinki Helsinki, Finland.
Department of Neuroscience, Karolinska Institutet Stockholm, Sweden.
Front Behav Neurosci. 2014 Sep 12;8:315. doi: 10.3389/fnbeh.2014.00315. eCollection 2014.
Developmental exposure to low dose of methylmercury (MeHg) has a long-lasting effect on memory and attention deficits in humans, as well as cognitive performance, depression-like behavior and the hippocampal levels of the brain-derived neurotrophic factor (Bdnf)in mice. The Bdnf receptor TrkB is a key player of Bdnf signaling. Using transgenic animals, here we analyzed the effect of the full-length TrkB overexpression (TK+) on behavior impairments induced by perinatal MeHg. TK overexpression in the MeHg-exposed mice enhanced generalized anxiety and cue memory in the fear conditioning (FC) test. Early exposure to MeHg induced deficits in reversal spatial memory in the Morris water maze (MWM) test and depression-like behavior in the forced swim test (FST) in only wild-type (WT) mice but did not affect these parameters in TK+ mice. These changes were associated with TK+ effect on the increase in Bdnf 2, 3, 4 and 6 transcription in the hippocampus as well as with interaction of TK+ and MeHg factors for Bdnf 1, 9a and truncated TrkB.T1 transcripts in the prefrontal cortex. However, the MeHg-induced anxiety-like behavior in the elevated plus maze (EPM) and open field (OF) tests was ameliorated by TK+ background only in the OF test. Moreover, TK overexpression in the MeHg mice did not prevent significant stress-induced weight loss during the period of adaptation to individual housing in metabolic cages. These TK genotype-independent changes were primarily accompanied by the MeHg-induced hippocampal deficits in the activity-dependent Bdnf 1, 4 and 9a variants, TrkB.T1, and transcripts for important antioxidant enzymes glyoxalases Glo1 and Glo2 and glutathione reductase Gsr. Our data suggest a role of full-length TrkB in buffering against memory deficits and depression-like behavior in the MeHg mice but propose the involvement of additional pathways, such as the antioxidant system or TrkB.T1 signaling, in stress- or anxiety-related responses induced by developmental MeHg exposure.
发育过程中低剂量甲基汞（MeHg）暴露对人类的记忆和注意力缺陷、认知能力、抑郁样行为以及小鼠脑源性神经营养因子（Bdnf）的海马水平具有长期影响。Bdnf受体TrkB是Bdnf信号传导的关键参与者。在此，我们利用转基因动物分析了全长TrkB过表达（TK+）对围产期MeHg诱导的行为损伤的影响。在恐惧条件反射（FC）试验中，MeHg暴露小鼠中的TK过表达增强了广泛性焦虑和线索记忆。早期暴露于MeHg仅在野生型（WT）小鼠的莫里斯水迷宫（MWM）试验中诱导了空间记忆逆转缺陷，在强迫游泳试验（FST）中诱导了抑郁样行为，但对TK+小鼠的这些参数没有影响。这些变化与TK+对海马中Bdnf 2、3、4和6转录增加的影响以及前额叶皮层中TK+和MeHg因子对Bdnf 1、9a和截短的TrkB.T1转录本的相互作用有关。然而，仅在旷场试验（OF）中，TK+背景改善了MeHg在高架十字迷宫（EPM）和旷场试验中诱导的焦虑样行为。此外，MeHg小鼠中的TK过表达并不能防止在代谢笼中适应个体饲养期间由应激引起的显著体重减轻。这些与TK基因型无关的变化主要伴随着MeHg诱导的海马中活性依赖性Bdnf 1、4和9a变体、TrkB.T1以及重要抗氧化酶乙二醛酶Glo1和Glo2和谷胱甘肽还原酶Gsr转录本的缺陷。我们的数据表明全长TrkB在缓冲MeHg小鼠的记忆缺陷和抑郁样行为方面发挥作用，但提出在发育性MeHg暴露诱导的应激或焦虑相关反应中涉及其他途径，如抗氧化系统或TrkB.T1信号传导。
