Astrocyte-selective STAT3 knockdown rescues methamphetamine withdrawal-disrupted spatial memory in mice via restoring the astrocytic capacity of glutamate clearance in dCA1
Astrocyte-selective STAT3 knockdown rescues methamphetamine withdrawal-disrupted spatial memory in mice via restoring the astrocytic capacity of glutamate clearance in dCA1
复制标题
星形胶质细胞选择性 STAT3 敲除通过恢复 dCA1 中星形胶质细胞的谷氨酸清除能力来拯救小鼠的甲基苯丙胺戒断破坏的空间记忆
作者：
Pengbo Shi;Zhaosu Li;Teng He;Nanqin Li;Xing Xu;Peiyao Yu;Xue Lu;Jiaxun Nie;Dekang Liu;Qinglong Cai;Yun Guan;Feifei Ge;Jun Wang;Xiaowei Guan
甲基苯丙胺 (METH) 是一种常见的滥用药物。 METH 触发的背侧 CA1 (dCA1) 谷氨酸 (Glu) 水平可以部分解释 METH 引起的记忆异常的病因，但突触机制仍不清楚。在这里，我们发现冰毒戒断会扰乱小鼠的空间记忆，并伴随着 dCA1 突触处 Glu 水平和突触后神经元活动的增加。 METH 戒断削弱了星形胶质细胞中 Glu 清除的能力，如 A1 样星形胶质细胞和磷酸化信号转导器和转录激活剂 3 (p-STAT3) 的增加，减少 Glu 转运蛋白 1（GLT-1，也称为 EAAT2 或 SLC1A2）、Glu-天冬氨酸转运蛋白（GLAST 也称为 EAAT1 或 SLC1A3）和星形胶质细胞谷氨酰胺合酶。 (GS)，但未能影响 dCA1 内 dCA3 的突触前 Glu 释放。此外，我们发现体外 A1 样星形胶质细胞表现出 STAT3 激活增加和 Glu 清除能力受损。最重要的是，在体内选择性敲低 dCA1 中的星形胶质细胞 STAT3，恢复了星形胶质细胞清除 Glu 的能力，使 dCA1 突触的 Glu 水平正常化，并最终挽救了小鼠因冰毒戒断而中断的空间记忆。因此，星形细胞Glu清除系统，特别是STAT3，可作为未来治疗METH神经毒性的新靶点。
Methamphetamine (METH) is a common abused drug. METH‐triggered glutamate (Glu) levels in dorsal CA1 (dCA1) could partially explain the etiology of METH‐caused abnormal memory, but the synaptic mechanism remains unclear. Here, we found that METH withdrawal disrupted spatial memory in mice, accompanied by the increases in Glu levels and postsynaptic neuronal activities at dCA1 synapses. METH withdrawal weakened the capacity of Glu clearance in astrocytes, as indicated by increasing the A1‐like astrocytes and phosphorylated signal transducer and activator of transcription 3 (p‐STAT3), decreasing the Glu transporter 1(GLT‐1, also known as EAAT2 or SLC1A2), Glu‐aspartate‐transporter (GLAST also known as EAAT1 or SLC1A3) and astrocytic glutamine synthase (GS), but failed to affect the presynaptic Glu release from dCA3 within dCA1. Moreover, we identified that in vitro A1‐like astrocytes exhibited an increased STAT3 activation and the impaired capacity of Glu clearance. Most importantly, selective knockdown of astrocytic STAT3 in vivo in dCA1 restored the astrocytic capacity of Glu clearance, normalized Glu levels at dCA1 synapses, and finally rescued METH withdrawal‐disrupted spatial memory in mice. Thus, astrocytic Glu clearance system, especially STAT3, serves as a novel target for future therapies against METH neurotoxicity.