Adult glut3 homozygous null mice survive to demonstrate neural excitability and altered neurobehavioral responses reminiscent of neurodevelopmental disorders.
Adult glut3 homozygous null mice survive to demonstrate neural excitability and altered neurobehavioral responses reminiscent of neurodevelopmental disorders.
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DOI：
10.1016/j.expneurol.2021.113603
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发表时间：
2021-04
影响因子：
5.3
通讯作者：
Devaskar SU
中科院分区：
文献类型：
--
作者：
Shin BC;Cepeda C;Eghbali M;Byun SY;Levine MS;Devaskar SU
由于GLUT3对神经传递的供能至关重要，我们在体内研究了在谷氨酸兴奋性神经元中携带条件性纯合glut3基因突变（KO）的成年表型。这些KO小鼠在脑和体重方面表现出性别特异性差异（分别为p = 0.0001和p = 0.01），大脑皮质和脑干中的GLUT3蛋白减少（p = 0.005）。在膜片钳研究中，glut3 KO小鼠在应用GABAA拮抗剂时，锥体神经元出现发作活动的潜伏期缩短且发作活动增强（分别为p = 0.01和p = 0.015），支持了其高兴奋性。此外，神经行为的相关变化包括：在转棒运动测试中因协调不良而跌倒的潜伏期缩短，在旷场测试中总移动距离以及周边与中心区域相比移动距离增加，表明存在多动伴焦虑（雄性p = 0.0013，雌性p = 0.045），冻结时间减少，提示情境恐惧条件反射受损（p = 0.0033），在空间认知记忆水迷宫测试中目标象限停留时间减少（p = 0.034），社交性增强，特别是对新奇事物的社交性增强，反映出缺乏抑制/冲动性（p = 0.038）。这些特征中的一些在雄性和雌性中同样明显（认知方面），而其他特征则在雌性中出现（焦虑和冲动性）。我们得出结论，成年谷氨酸兴奋性神经元中的GLUT3对于维持神经传递平衡至关重要，该平衡调节兴奋，同时维持运动协调和活动、认知、空间记忆以及对情境事件和新奇事物的正常恐惧，并调节社交性。虽然这些行为中的一些存在性别特异性，但我们的研究结果共同表明，功能缺失的glut3基因突变或多态性可能是注意缺陷多动障碍内表型的基础。
Since GLUT3 is vital for fueling neurotransmission, we examined in-vivo the adult phenotype carrying the conditional homozygous glut3 gene mutation (KO) in glutamate-excitatory neurons. These KO mice demonstrated sex-specific differences in brain and body weights (p=0.0001 and p=0.01 each) with reduced GLUT3 protein in cerebral cortices and brain stem (p=0.005). In patch clamp studies the glut3 KO mice displayed a shorter latency to and enhanced paroxysmal activity (p=0.01 and p=0.015 each) in pyramidal neurons upon application of a GABAA antagonist, supporting hyperexcitability. Further, associated changes in neurobehavior consisted of reduced latency to fall in the rotorod motor test related to incoordination, increased distance travelled in total and periphery versus center in open field testing suggesting hyperactivity with anxiety (p=0.0013 in male, p=0.045 in female), reduced time freezing reminiscent of disrupted contextual fear conditioning (p=0.0033), decreased time in target quadrant seen with spatial cognitive memory water maze testing (p=0.034), and enhanced sociability particularly for novelty reflecting a lack of inhibition/impulsivity (p=0.038). Some of these features were equally pronounced in males and females (cognitive) while others were seen in females (anxiety and impulsivity). We conclude that GLUT3 in adult glutamate-excitatory neurons is essential for maintaining neurotransmitory equipoise regulating excitation with maintenance of motor coordination and activity, cognition, spatial memory and normal fear for both contextual events and novelty with tempered sociability. While sex-specificity was forthcoming for some of these behaviors, our findings collectively suggest that loss-of-function glut3 gene mutations or polymorphisms may underlie an endophenotype of attention deficit-hyperactivity disorder.
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发表时间：
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