Major depressive disorder (MDD) is a leading cause of disability worldwide, with a poorly known pathophysiology and sub-optimal treatment, based on serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitors. We review existing theories on MDD, paying special attention to the role played by the ventral anterior cingulate cortex (vACC) or its rodent equivalent, infralimbic cortex (IL), which tightly control the activity of brainstem monoamine neurons (including raphe 5-HT neurons) via descending afferents. Further, astrocytes regulate excitatory synapse activity via glutamate reuptake through astrocytic transporters EAAT1 and EAAT2 (GLAST and GLT-1 in rodents), and alterations of astrocyte number/function have been reported in MDD patients and suicide victims. We recently assessed the impact of reducing GLAST/GLT-1 function in IL on emotional behavior and serotonergic function in rodents. The acute pharmacological blockade of GLT-1 with dihydrokainate (DHK) in rat IL evoked an antidepressant-like effect mediated by local AMPA-R activation and a subsequent enhancement of serotonergic function. No effects were produced by DHK microinfusion in prelimbic cortex (PrL). In the second model, a moderate small interfering RNAs (siRNA)-induced reduction of GLAST and GLT-1 expression in mouse IL markedly increased local glutamatergic neurotransmission and evoked a depressive-like phenotype (reversed by citalopram and ketamine), and reduced serotonergic function and BDNF expression in cortical/hippocampal areas. As for DHK, siRNA microinfusion in PrL did not evoke behavioral/neurochemical effects. Overall, both studies support a critical role of the astrocyte-neuron communication in the control of excitatory neurotransmission in IL, and subsequently, on emotional behavior, via the downstream associated changes on serotonergic function.

中文翻译：

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星形胶质细胞对谷氨酸能活动的控制：对血清素能功能和情绪行为的下游影响。

基于5-羟色胺（5-羟色胺，5-HT）再摄取抑制剂，重度抑郁症（MDD）是世界范围内导致残疾的主要原因，其病理生理学和欠佳的治疗方法广为人知。我们回顾了有关MDD的现有理论，特别注意腹侧前扣带回皮层（vACC）或啮齿类动物等效肢体下层皮层（IL）所起的作用，后者严格控制脑干单胺神经元（包括5-HT 5-神经元）的活动）通过降序传入。此外，星形胶质细胞通过星形胶质转运蛋白EAAT1和EAAT2（啮齿类动物中的GLAST和GLT-1）通过谷氨酸重新摄取来调节兴奋性突触活性，据报道在MDD患者和自杀者中星形胶质细胞数量/功能发生了改变。我们最近评估了降低IL中GLAST / GLT-1功能对啮齿动物情绪行为和血清素能功能的影响。在大鼠IL中用二氢海藻酸酯（DHK）对GLT-1进行的急性药理阻断引起了局部AMPA-R激活介导的抗抑郁样作用，并随后增强了血清素能功能。DHK微输注前缘皮质（PrL）不会产生任何影响。在第二种模型中，小鼠IL中中等程度的小干扰RNA（siRNA）诱导的GLAST和GLT-1表达降低明显增加了局部谷氨酸能神经传递，并引起了抑郁样表型（被西酞普兰和氯胺酮逆转），并降低了血清素能功能/ BDNF在皮层/海马区的表达。至于DHK，PrL中的siRNA微输注没有引起行为/神经化学作用。全面的，