Targeting Glia with N-Acetylcysteine Modulates Brain Glutamate and Behaviors Relevant to Neurodevelopmental Disorders in C57BL/6J Mice.
Targeting Glia with N-Acetylcysteine Modulates Brain Glutamate and Behaviors Relevant to Neurodevelopmental Disorders in C57BL/6J Mice.
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DOI：
10.3389/fnbeh.2015.00343
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发表时间：
2015
影响因子：
3
通讯作者：
McAlonan G
中科院分区：
文献类型：
--
作者：
Durieux AM;Fernandes C;Murphy D;Labouesse MA;Giovanoli S;Meyer U;Li Q;So PW;McAlonan G
兴奋性(E)谷氨酸和抑制性(I)GABA传递之间的失衡可能是自闭症谱系障碍(ASD)和精神分裂症等神经发育疾病的基础。这可能是直接的，通过突触基因的改变，但越来越多的证据表明，通过神经胶质机制间接调节E/I平衡的重要性。在这里，我们使用C57BL/6J小鼠来验证纹状体谷氨酸水平可以被作用于神经胶质细胞的半胱氨酸-谷氨酸逆向转运体的N-乙酰半胱氨酸(NAC)所改变的假设。用质子磁共振波谱对纹状体谷氨酸进行体内定量。NAC对ASD相关行为的影响在一个单独的队列中进行了检验。NAC诱导纹状体谷氨酸呈时间依赖性下降，这概括了ASD中报道的纹状体谷氨酸降低的结果。NAC处理的动物在旷场测试中明显不那么活跃，更焦虑；NAC处理的雌性动物显著削弱了对惊吓反应的脉冲前抑制。这至少在一定程度上模仿了神经发育障碍中报道的更严重的焦虑和感觉运动门控受损。因此，神经胶质机制敏锐地调节谷氨酸，甚至在成年后也会产生功能上的影响。神经胶质细胞可能是一个潜在的药物靶点，用于开发治疗终生神经发育障碍的新疗法。
An imbalance between excitatory (E) glutamate and inhibitory (I) GABA transmission may underlie neurodevelopmental conditions such as autism spectrum disorder (ASD) and schizophrenia. This may be direct, through alterations in synaptic genes, but there is increasing evidence for the importance of indirect modulation of E/I balance through glial mechanisms. Here, we used C57BL/6J mice to test the hypothesis that striatal glutamate levels can be shifted by N-acetylcysteine (NAC), which acts at the cystine-glutamate antiporter of glial cells. Striatal glutamate was quantified in vivo using proton magnetic resonance spectroscopy. The effect of NAC on behaviors relevant to ASD was examined in a separate cohort. NAC induced a time-dependent decrease in striatal glutamate, which recapitulated findings of lower striatal glutamate reported in ASD. NAC-treated animals were significantly less active and more anxious in the open field test; and NAC-treated females had significantly impaired prepulse inhibition of startle response. This at least partly mimics greater anxiety and impaired sensorimotor gating reported in neurodevelopmental disorders. Thus glial mechanisms regulate glutamate acutely and have functional consequences even in adulthood. Glial cells may be a potential drug target for the development of new therapies for neurodevelopmental disorders across the life-span.
影响因子：
5.3
作者：
Domercq M;Vazquez-Villoldo N;Matute C
通讯作者：
Matute C