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首页> 外文期刊>The European Journal of Neuroscience >Genetic mapping of ASIC4 and contrasting phenotype to ASIC1a in modulating innate fear and anxiety
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Genetic mapping of ASIC4 and contrasting phenotype to ASIC1a in modulating innate fear and anxiety

机译：ASIC4的遗传作图和表型与ASIC1a的对比，以调节先天性恐惧和焦虑

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Although ASIC4 is a member of the acid-sensing ion channel (ASIC) family, we have limited knowledge of its expression and physiological function invivo. To trace the expression of this ion channel, we generated the ASIC4-knockout/CreERT(2)-knockin (Asic4(CreERT2)) mouse line. After tamoxifen induction in the Asic4(CreERT2)::CAG-STOPfloxed-Td-tomato double transgenic mice, we mapped the expression of ASIC4 at the cellular level in the central nervous system (CNS). ASIC4 was expressed in many brain regions, including the olfactory bulb, cerebral cortex, striatum, hippocampus, amygdala, thalamus, hypothalamus, brain stem, cerebellum, spinal cord and pituitary gland. Colocalisation studies further revealed that ASIC4 was expressed mainly in three types of cells in the CNS: (i) calretinin (CR)-positive and/or vasoactive intestine peptide (VIP)-positive interneurons; (ii) neural/glial antigen2 (NG2)-positive glia, also known as oligodendrocyte precursor cells; and (iii) cerebellar granule cells. To probe the possible role of ASIC4, we hypothesised that ASIC4 could modulate the membrane expression of ASIC1a and thus ASIC1a signaling invivo. We conducted behavioral phenotyping of Asic4(CreERT2) mice by screening many of the known behavioral phenotypes found in Asic1a knockouts and found ASIC4 not involved in shock-evoked fear learning and memory, seizure termination or psychostimulant-induced locomotion/rewarding effects. In contrast, ASIC4 might play an important role in modulating the innate fear response to predator odor and anxious state because ASIC4-mutant mice showed increased freezing response to 2,4,5-trimethylthiazoline and elevated anxiety-like behavior in both the open-field and elevated-plus maze. ASIC4 may modulate fear and anxiety by counteracting ASIC1a activity in the brain.
机译：尽管ASIC4是酸敏感离子通道（ASIC）家族的成员，但我们对其表达和体内生理功能的了解有限。为了追踪该离子通道的表达，我们生成了ASIC4-knockout / CreERT（2）-knockin（Asic4（CreERT2））小鼠系。他莫昔芬诱导Asic4（CreERT2）:: CAG-STOPfloxed-Td-tomato双转基因小鼠后，我们绘制了ASIC4在中枢神经系统（CNS）细胞水平的表达图。 ASIC4在许多大脑区域表达，包括嗅球，大脑皮层，纹状体，海马，杏仁核，丘脑，下丘脑，脑干，小脑，脊髓和垂体。共定位研究进一步表明，ASIC4主要在中枢神经系统的三种类型的细胞中表达：（i）钙网蛋白（CR）阳性和/或血管活性肠肽（VIP）阳性中神经元; （ii）神经/神经胶质抗原2（NG2）阳性神经胶质细胞，也称为少突胶质细胞前体细胞; （iii）小脑颗粒细胞。为了探究ASIC4的可能作用，我们假设ASIC4可以调节ASIC1a的膜表达，从而调节ASIC1a的体内信号传导。我们通过筛查在Asic1a基因敲除中发现的许多已知行为表型，对Asic4（CreERT2）小鼠进行了行为表型研究，发现ASIC4不参与休克诱发的恐惧学习和记忆，癫痫发作终止或精神刺激诱发的运动/奖励作用。相比之下，ASIC4可能在调节对捕食者气味和焦虑状态的先天恐惧反应中起重要作用，因为ASIC4突变型小鼠在户外均表现出对2,4,5-三甲基噻唑啉的冰冻反应增强和焦虑样行为升高和高架迷宫。 ASIC4可以通过抵消ASIC1a在大脑中的活动来调节恐惧和焦虑。

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