Alterations of energy metabolism and of astrocyte number/function in ventral anterior cingulate cortex (vACC) have been reported in major depressive disorder (MDD) patients and may contribute to MDD pathophysiology. We recently developed a mouse model of MDD mimicking these alterations. We knocked down the astroglial glutamate transporters GLAST and GLT-1 in infralimbic cortex (IL, rodent equivalent of vACC) using small interfering RNA (siRNA). GLAST and GLT-1 siRNA microinfusion in IL evoked a depressive-like phenotype, associated with a reduced serotonergic function and reduced forebrain BDNF expression. Neither effect occurred after siRNA application in the adjacent prelimbic cortex (PrL), thus emphasizing the critical role of vACC/IL in MDD pathogenesis. Here we examined the cellular/network basis of the changes induced in IL using intracellular recordings of layer V pyramidal neurons from mice microinjected with siRNA 24 h before. We analyzed (i) the electrophysiological characteristics of neurons; (ii) the synaptic transmission properties, by monitoring miniature, spontaneous and evoked EPSCs, and (iii) the gliotransmission, by monitoring slow inward currents (SICs), mediated by astrocytic glutamate release and activation of extra-synaptic NMDA receptors. GLT-1 and GLAST knockdown led to a more depolarized membrane potential and increased action potential firing rate of layer V pyramidal neurons, and enhanced excitatory synaptic transmission, as shown by the enhanced amplitude/frequency of spontaneous EPSCs. Gliotransmission was also increased, as indicated by the enhanced SIC amplitude/frequency. Hence, the depressive-like phenotype is associated with IL hyperactivity, likely leading to an excessive top-down inhibitory control of serotonergic activity through IL-midbrain descending pathways.

中文翻译：

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星形胶质细胞谷氨酸转运蛋白 GLT-1 和 GLAST 的体内敲低增加了小鼠边缘下皮层的兴奋性神经传递：与抑郁样表型的相关性

据报道，在重度抑郁症 (MDD) 患者中，能量代谢和腹侧前扣带回皮层 (vACC) 中的星形胶质细胞数量/功能发生了改变，并且可能导致 MDD 的病理生理学。我们最近开发了一种模仿这些改变的 MDD 小鼠模型。我们使用小干扰 RNA (siRNA) 敲低了边缘下皮层（IL，啮齿动物等效于 vACC）中的星形胶质细胞谷氨酸转运蛋白 GLAST 和 GLT-1。IL 中的 GLAST 和 GLT-1 siRNA 微量输注引起抑郁样表型，与血清素功能降低和前脑 BDNF 表达降低相关。在相邻的前边缘皮层 (PrL) 中应用 siRNA 后，两种效果均未发生，因此强调了 vACC/IL 在 MDD 发病机制中的关键作用。在这里，我们使用 24 小时前显微注射 siRNA 的小鼠的 V 层锥体神经元的细胞内记录检查了 IL 中诱导的变化的细胞/网络基础。我们分析了（i）神经元的电生理特征；(ii) 突触传递特性，通过监测微型、自发和诱发的 EPSC，以及 (iii) 胶质传递，通过监测由星形胶质细胞谷氨酸释放和突触外 NMDA 受体激活介导的缓慢内向电流 (SIC)。GLT-1 和 GLAST 敲低导致更去极化的膜电位和 V 层锥体神经元的动作电位放电率增加，并增强兴奋性突触传递，如自发性 EPSC 的增强幅度/频率所示。Gliotransmission 也增加了，如增强的 SIC 幅度/频率所示。因此，抑郁样表型与 IL 过度活跃有关，可能导致通过 IL 中脑下行通路过度自上而下抑制血清素能活性。