Pfaffenseller Bianca, Kapczinski Flavio, Gallitano Amelia L, Klamt Fábio
Laboratory of Molecular Psychiatry, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
Department of Psychiatry and Behavioral Neurosciences, McMaster University, Hamilton, ON, Canada.
Front Behav Neurosci. 2018 Feb 5;12:15. doi: 10.3389/fnbeh.2018.00015. eCollection 2018.
Bipolar disorder (BD) is a severe psychiatric illness with a consistent genetic influence, involving complex interactions between numerous genes and environmental factors. Immediate early genes (IEGs) are activated in the brain in response to environmental stimuli, such as stress. The potential to translate environmental stimuli into long-term changes in brain has led to increased interest in a potential role for these genes influencing risk for psychiatric disorders. Our recent finding using network-based approach has shown that the regulatory unit of early growth response gene 3 () of IEGs family was robustly repressed in postmortem prefrontal cortex of BD patients. As a central transcription factor, EGR3 regulates an array of target genes that mediate critical neurobiological processes such as synaptic plasticity, memory and cognition. Considering that expression is induced by brain-derived neurotrophic factor (BDNF) that has been consistently related to BD pathophysiology, we suggest a link between BDNF and EGR3 and their potential role in BD. A growing body of data from our group and others has shown that peripheral BDNF levels are reduced during mood episodes and also with illness progression. In this same vein, BDNF has been proposed as an important growth factor in the impaired cellular resilience related to BD. Taken together with the fact that EGR3 regulates the expression of the neurotrophin receptor p75NTR and may also indirectly induce BDNF expression, here we propose a feed-forward gene regulatory network involving EGR3 and BDNF and its potential role in BD.
双相情感障碍（BD）是一种具有持续遗传影响的严重精神疾病，涉及众多基因与环境因素之间的复杂相互作用。即刻早期基因（IEGs）在大脑中会因环境刺激（如应激）而被激活。将环境刺激转化为大脑长期变化的潜力，引发了人们对这些基因在影响精神疾病风险方面潜在作用的更多关注。我们最近基于网络的研究发现表明，即刻早期基因家族的早期生长反应基因3（EGR3）的调控单元在双相情感障碍患者的死后前额叶皮质中受到强烈抑制。作为一种核心转录因子，EGR3调控一系列靶基因，这些靶基因介导诸如突触可塑性、记忆和认知等关键神经生物学过程。鉴于EGR3的表达是由与双相情感障碍病理生理学一直相关的脑源性神经营养因子（BDNF）诱导的，我们提出BDNF与EGR3之间存在联系，以及它们在双相情感障碍中的潜在作用。我们团队和其他团队越来越多的数据表明，在情绪发作期间以及随着疾病进展，外周BDNF水平会降低。同样，BDNF已被认为是与双相情感障碍相关的细胞弹性受损中的一种重要生长因子。结合EGR3调控神经营养因子受体p75NTR的表达且可能还间接诱导BDNF表达这一事实，我们在此提出一个涉及EGR3和BDNF的前馈基因调控网络及其在双相情感障碍中的潜在作用。
