Deficit of neuronal EAAT2 impairs hippocampus CA3 neuron’s activity and may induce depressive like behaviors

IF 11.4 1区 综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES Journal of Advanced Research Pub Date : 2025-03-15 DOI:10.1016/j.jare.2025.03.016
Ke Cheng, Chong Chen, Qinji Zhou, Xiangyu Chen, Peng Xie
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Abstract

Introduction

Major depressive disorder (MDD) is a severe neuropsychiatric disease that is accompanied by hippocampal dysfunction. Currently, the complex neuronal types and molecules involved in the various hippocampal subfields in patients with depression remain unclear.

Objectives

We focused on the role of hippocampal excitatory amino acid transporter 2 (EAAT2) in chronic stress.

Methods

We studied two chronic stress models, the chronic unpredictable mild stress (CUMS) and the chronic social defeat stress (CSDS) models, and performed pharmacological inhibition, genetic manipulations to examine overexpression of neuron-specific solute carrier family 1 member 2 (SLC1A2), the gene encoding EAAT2, in the dorsal CA3 and conditional Slc1a2 knockout in CA3, whole-cell recording, and behavioral tests.

Results

Our results indicated that decreased EAAT2 expression and specific inhibition were associated with depression-like behavior and enhanced CA3 pyramidal neuron activity. In addition, neuron-specific EAAT2 overexpression in the CA3 yielded antidepressant-like effects and inhibited CA3 pyramidal neuron hyperactivity, whereas conditional CA3 EAAT2 knockout showed opposite effects at both behavioral and functional levels. We also found that the single-nucleotide polymorphism, rs77619780, in the SLCA1A2 gene was associated with lower MDD risk.

Conclusion

Our findings revealed that EAAT2 deficit in the CA3 induces depression-like behavior, which offers novel insight into MDD pathophysiology.

Abstract Image

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引言 重度抑郁症(MDD)是一种严重的神经精神疾病,伴有海马功能障碍。目前,抑郁症患者的海马亚区中涉及的复杂神经元类型和分子仍不清楚。目的我们重点研究了海马兴奋性氨基酸转运体 2(EAAT2)在慢性应激中的作用。方法我们研究了两种慢性应激模型,即慢性不可预知轻度应激(CUMS)和慢性社会挫败应激(CSDS)模型,并进行了药物抑制、基因操作以检测神经元特异性溶质载体家族 1 成员 2(SLC1A2)(编码 EAAT2 的基因)在 CA3 背侧的过表达和 CA3 中条件性 Slc1a2 基因敲除、全细胞记录和行为测试。结果我们的研究结果表明,EAAT2表达和特异性抑制的减少与抑郁样行为和CA3锥体神经元活动增强有关。此外,CA3神经元特异性EAAT2过表达可产生抗抑郁样效应并抑制CA3锥体神经元的过度活动,而条件性CA3 EAAT2敲除则在行为和功能水平上显示出相反的效应。我们还发现,SLCA1A2 基因中的单核苷酸多态性 rs77619780 与较低的 MDD 风险相关。
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来源期刊
Journal of Advanced Research
Journal of Advanced Research Multidisciplinary-Multidisciplinary
CiteScore
21.60
自引率
0.90%
发文量
280
审稿时长
12 weeks
期刊介绍: Journal of Advanced Research (J. Adv. Res.) is an applied/natural sciences, peer-reviewed journal that focuses on interdisciplinary research. The journal aims to contribute to applied research and knowledge worldwide through the publication of original and high-quality research articles in the fields of Medicine, Pharmaceutical Sciences, Dentistry, Physical Therapy, Veterinary Medicine, and Basic and Biological Sciences. The following abstracting and indexing services cover the Journal of Advanced Research: PubMed/Medline, Essential Science Indicators, Web of Science, Scopus, PubMed Central, PubMed, Science Citation Index Expanded, Directory of Open Access Journals (DOAJ), and INSPEC.
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