Since the discovery of ketamine anti-depressant effects in last decade, it has effectively revitalized interest in investigating excitatory synapses hypothesis in the pathogenesis of depression. In the present study, we aimed to reveal the excitatory synaptic regulation of corticotropin-releasing hormone (CRH) neuron in the hypothalamus, which is the driving force in hypothalamic–pituitary–adrenal (HPA) axis regulation. This study constitutes the first observation of an increased density of PSD-93-CRH co-localized neurons in the hypothalamic paraventricular nucleus (PVN) of patients with major depression. PSD-93 overexpression in CRH neurons in the PVN induced depression-like behaviors in mice, accompanied by increased serum corticosterone level. PSD-93 knockdown relieved the depression-like phenotypes in a lipopolysaccharide (LPS)-induced depression model. Electrophysiological data showed that PSD-93 overexpression increased CRH neurons synaptic activity, while PSD-93 knockdown decreased CRH neurons synaptic activity. Furthermore, we found that LPS induced increased the release of glutamate from microglia to CRH neurons resulted in depression-like behaviors using fiber photometry recordings. Together, these results show that PSD-93 is involved in the pathogenesis of depression via increasing the synaptic activity of CRH neurons in the PVN, leading to the hyperactivity of the HPA axis that underlies depression-like behaviors.

自从在过去十年中发现氯胺酮抗抑郁作用以来，它有效地激发了人们对研究抑郁症发病机制中兴奋性突触假说的兴趣。在本研究中，我们旨在揭示下丘脑促肾上腺皮质激素释放激素 (CRH) 神经元的兴奋性突触调节，这是下丘脑-垂体-肾上腺 (HPA) 轴调节的驱动力。这项研究首次观察到重度抑郁症患者下丘脑室旁核 (PVN) 中 PSD-93-CRH 共定位神经元的密度增加。PVN 中 CRH 神经元中 PSD-93 的过表达诱导小鼠出现抑郁样行为，并伴有血清皮质酮水平升高。PSD-93 敲低缓解了脂多糖 (LPS) 诱导的抑郁模型中的抑郁样表型。电生理数据显示 PSD-93 过表达增加 CRH 神经元突触活动，而 PSD-93 敲低降低 CRH 神经元突触活动。此外，我们发现 LPS 诱导增加的谷氨酸从小胶质细胞释放到 CRH 神经元导致使用纤维光度记录的抑郁样行为。总之，这些结果表明，PSD-93 通过增加 PVN 中 CRH 神经元的突触活动参与抑郁症的发病机制，导致作为抑郁样行为基础的 HPA 轴过度活跃。而 PSD-93 敲低降低了 CRH 神经元的突触活动。此外，我们发现 LPS 诱导增加的谷氨酸从小胶质细胞释放到 CRH 神经元导致使用纤维光度记录的抑郁样行为。总之，这些结果表明，PSD-93 通过增加 PVN 中 CRH 神经元的突触活动参与抑郁症的发病机制，导致作为抑郁样行为基础的 HPA 轴过度活跃。而 PSD-93 敲低降低了 CRH 神经元的突触活动。此外，我们发现 LPS 诱导增加的谷氨酸从小胶质细胞释放到 CRH 神经元导致使用纤维光度记录的抑郁样行为。总之，这些结果表明，PSD-93 通过增加 PVN 中 CRH 神经元的突触活动参与抑郁症的发病机制，导致作为抑郁样行为基础的 HPA 轴过度活跃。