Li Ye, Fan Cuiqin, Wang Changmin, Wang Liyan, Yi Yuhang, Mao Xueqin, Chen Xiao, Lan Tian, Wang Wenjing, Yu Shu Yan
Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, PR China.
Morphological Experimental Center, Shandong University, School of Basic Medical Sciences, 44 Wenhuaxilu Road, Jinan, Shandong 250012, PR China.
Sci Adv. 2022 Nov 11;8(45):eadd7063. doi: 10.1126/sciadv.add7063.
Major depression disorder (MDD) is a neuropsychiatric disorder characterized by abnormal neuronal activity in specific brain regions. A factor that is crucial in maintaining normal neuronal functioning is intracellular pH (pHi) homeostasis. In this study, we show that chronic stress, which induces depression-like behaviors in animal models, down-regulates the expression of the hippocampal Na/H exchanger isoform 1, NHE1, a major determinant of pHi in neurons. Knockdown of NHE1 in CA1 hippocampal pyramidal neurons leads to intracellular acidification, promotes dendritic spine loss, lowers excitatory synaptic transmission, and enhances the susceptibility to stress exposure in rats. Moreover, E3 ubiquitin ligase cullin4A may promote ubiquitination and degradation of NHE1 to induce these effects of an unbalanced pHi on synaptic processes. Electrophysiological data further suggest that the abnormal excitability of hippocampal neurons caused by maladaptation of neuroplasticity may be involved in the pathogenesis of this disease. These findings elucidate a mechanism for pHi homeostasis alteration as related to MDD.
重度抑郁症（MDD）是一种神经精神疾病，其特征是特定脑区的神经元活动异常。维持正常神经元功能的一个关键因素是细胞内pH值（pHi）稳态。在本研究中，我们表明，在动物模型中诱发抑郁样行为的慢性应激会下调海马钠/氢交换体同工型1（NHE1）的表达，NHE1是神经元中pHi的主要决定因素。在大鼠海马CA1锥体神经元中敲低NHE1会导致细胞内酸化，促进树突棘丢失，降低兴奋性突触传递，并增强对应激暴露的易感性。此外，E3泛素连接酶cullin4A可能促进NHE1的泛素化和降解，从而诱导pHi失衡对突触过程产生这些影响。电生理数据进一步表明，神经可塑性适应不良导致的海马神经元异常兴奋性可能参与了该疾病的发病机制。这些发现阐明了与MDD相关的pHi稳态改变机制。
