Astroglial glutamate transporter deficiency increases synaptic excitability and leads to pathological repetitive behaviors in mice.
Astroglial glutamate transporter deficiency increases synaptic excitability and leads to pathological repetitive behaviors in mice.
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DOI：
10.1038/npp.2015.26
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发表时间：
2015-06
期刊：
影响因子：
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通讯作者：
Tanaka K
中科院分区：
文献类型：
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作者：
Aida T;Yoshida J;Nomura M;Tanimura A;Iino Y;Soma M;Bai N;Ito Y;Cui W;Aizawa H;Yanagisawa M;Nagai T;Takata N;Tanaka KF;Takayanagi R;Kano M;Götz M;Hirase H;Tanaka K
细胞兴奋与抑制之比（E/I 比）的增加被认为是神经精神疾病的发病机制，例如自闭症谱系障碍 (ASD)、强迫症 (OCD) 和抽动秽语综合征 (TS)。适当的 E/I 比率是通过神经元和神经胶质细胞中表达的因子实现的。在星形胶质细胞中，谷氨酸转运蛋白 GLT1 对于调节 E/I 比率至关重要。然而，GLT1 功能障碍在神经精神疾病发病机制中的作用仍不清楚，因为 GLT1 完全缺乏的小鼠表现出癫痫发作和过早死亡。在这里，我们发现星形胶质细胞特异性 GLT1 诱导敲除 (GLASTCreERT2/+/GLT1flox/flox，iKO) 小鼠表现出病理性重复行为，包括过度和伤害性的自我梳理和抽动样摇头。电生理学研究表明，皮质纹状体突触的兴奋性传递在基础状态下是正常的，但在重复刺激后会增加。此外，用 N-甲基-D-天冬氨酸 (NMDA) 受体拮抗剂美金刚治疗可改善 iKO 小鼠的病理性重复行为。这些结果表明星形胶质细胞 GLT1 在控制皮质纹状体突触的突触功效方面具有关键作用，其功能障碍会导致病理性重复行为。
An increase in the ratio of cellular excitation to inhibition (E/I ratio) has been proposed to underlie the pathogenesis of neuropsychiatric disorders, such as autism spectrum disorders (ASD), obsessive-compulsive disorder (OCD), and Tourette's syndrome (TS). A proper E/I ratio is achieved via factors expressed in neuron and glia. In astrocytes, the glutamate transporter GLT1 is critical for regulating an E/I ratio. However, the role of GLT1 dysfunction in the pathogenesis of neuropsychiatric disorders remains unknown because mice with a complete deficiency of GLT1 exhibited seizures and premature death. Here, we show that astrocyte-specific GLT1 inducible knockout (GLASTCreERT2/+/GLT1flox/flox, iKO) mice exhibit pathological repetitive behaviors including excessive and injurious levels of self-grooming and tic-like head shakes. Electrophysiological studies reveal that excitatory transmission at corticostriatal synapse is normal in a basal state but is increased after repetitive stimulation. Furthermore, treatment with an N-methyl-D-aspartate (NMDA) receptor antagonist memantine ameliorated the pathological repetitive behaviors in iKO mice. These results suggest that astroglial GLT1 has a critical role in controlling the synaptic efficacy at corticostriatal synapses and its dysfunction causes pathological repetitive behaviors.