Variants in Ion Channel Genes Link Phenotypic Features of Bipolar Illness to Specific Neurobiological Process Domains.
Variants in Ion Channel Genes Link Phenotypic Features of Bipolar Illness to Specific Neurobiological Process Domains.
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DOI：
10.1159/000371886
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发表时间：
2015-05-01
期刊：
影响因子：
--
通讯作者：
Nurnberger, John I
中科院分区：
文献类型：
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作者：
Balaraman, Yokesh;Lahiri, Debomoy K;Nurnberger, John I
全基因组关联研究的最新进展指出了电压门控离子通道在神经精神疾病，特别是双相情感障碍（BD）中的重要作用。BD的表型是复杂的，在情绪发作期间有症状，并且在发作之间持续存在缺陷。我们试图阐明与离子通道信号传导相关的常见神经生物学机制，以便为BD患者的临床症状和可能的内在表型提供新的视角。我们提出了一个模型，在该模型中，编码离子通道蛋白的基因的多个变体会扰乱激励电路，突触可塑性，髓鞘形成，下丘脑-垂体-肾上腺轴功能，昼夜神经元节律和能量调节。神经生物学机制的这些变化将表现在异常奖赏处理、白色物质高信号、执行功能缺陷、额边缘连接改变、杏仁核活性增加、褪黑素抑制增加、REM潜伏期减少和异常肌醇/ATP穿梭的内表型中。内表型导致不良冲动控制、动机变化、认知缺陷、异常应激反应、睡眠障碍和涉及不同神经生物学过程域的能量变化的行为。该假说认为，这些障碍始于发育过程中神经回路的改变，随后多种环境触发因素可能通过活动依赖性分子过程破坏神经元兴奋性平衡，导致临床情绪发作。
Recent advances in genome-wide association studies are pointing towards a major role for voltage-gated ion channels in neuropsychiatric disorders and, in particular, bipolar disorder (BD). The phenotype of BD is complex, with symptoms during mood episodes and deficits persisting between episodes. We have tried to elucidate the common neurobiological mechanisms associated with ion channel signaling in order to provide a new perspective on the clinical symptoms and possible endophenotypes seen in BD patients. We propose a model in which the multiple variants in genes coding for ion channel proteins would perturb motivational circuits, synaptic plasticity, myelination, hypothalamic-pituitary-adrenal axis function, circadian neuronal rhythms, and energy regulation. These changes in neurobiological mechanisms would manifest in endophenotypes of aberrant reward processing, white matter hyperintensities, deficits in executive function, altered frontolimbic connectivity, increased amygdala activity, increased melatonin suppression, decreased REM latency, and aberrant myo-inositol/ATP shuttling. The endophenotypes result in behaviors of poor impulse control, motivational changes, cognitive deficits, abnormal stress response, sleep disturbances, and energy changes involving different neurobiological process domains. The hypothesis is that these disturbances start with altered neural circuitry during development, following which multiple environmental triggers may disrupt the neuronal excitability balance through an activity-dependent molecular process, resulting in clinical mood episodes.