C3aR in the medial prefrontal cortex modulates the susceptibility to LPS-induced depressive-like behaviors through glutamatergic neuronal excitability

IF 6.7 2区 医学 Q1 NEUROSCIENCES Progress in Neurobiology Pub Date : 2024-04-17 DOI:10.1016/j.pneurobio.2024.102614
Rui Sun , Meng-Yu Tang , Dan Yang , Yan-Yi Zhang , Yi-Heng Xu , Yong Qiao , Bin Yu , Shu-Xia Cao , Hao Wang , Hui-Qian Huang , Hong Zhang , Xiao-Ming Li , Hong Lian
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Abstract

Complement activation and prefrontal cortical dysfunction both contribute to the pathogenesis of major depressive disorder (MDD), but their interplay in MDD is unclear. We here studied the role of complement C3a receptor (C3aR) in the medial prefrontal cortex (mPFC) and its influence on depressive-like behaviors induced by systematic lipopolysaccharides (LPS) administration. C3aR knockout (KO) or intra-mPFC C3aR antagonism confers resilience, whereas C3aR expression in mPFC neurons makes KO mice susceptible to LPS-induced depressive-like behaviors. Importantly, the excitation and inhibition of mPFC neurons have opposing effects on depressive-like behaviors, aligning with increased and decreased excitability by C3aR deletion and activation in cortical neurons. In particular, inhibiting mPFC glutamatergic (mPFCGlu) neurons, the main neuronal subpopulation expresses C3aR, induces depressive-like behaviors in saline-treated WT and KO mice, but not in LPS-treated KO mice. Compared to hypoexcitable mPFCGlu neurons in LPS-treated WT mice, C3aR-null mPFCGlu neurons display hyperexcitability upon LPS treatment, and enhanced excitation of mPFCGlu neurons is anti-depressant, suggesting a protective role of C3aR deficiency in these circumstances. In conclusion, C3aR modulates susceptibility to LPS-induced depressive-like behaviors through mPFCGlu neuronal excitability. This study identifies C3aR as a pivotal intersection of complement activation, mPFC dysfunction, and depression and a promising therapeutic target for MDD.

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内侧前额叶皮层中的 C3aR 通过谷氨酸能神经元兴奋性调节对 LPS 诱导的抑郁样行为的易感性
补体激活和前额叶皮质功能障碍都是重性抑郁障碍(MDD)的发病机制,但它们在MDD中的相互作用尚不清楚。我们在此研究了补体C3a受体(C3aR)在内侧前额叶皮层(mPFC)中的作用及其对系统性脂多糖(LPS)给药诱导的抑郁样行为的影响。C3aR基因敲除(KO)或内侧前额叶皮层C3aR拮抗可赋予小鼠恢复能力,而mPFC神经元中C3aR的表达则使KO小鼠易受LPS诱导的抑郁样行为的影响。重要的是,mPFC神经元的兴奋和抑制对抑郁样行为的影响是相反的,这与皮质神经元中C3aR缺失和激活导致的兴奋性增高和降低是一致的。特别是,抑制 mPFC 谷氨酸能(mPFCGlu)神经元(表达 C3aR 的主要神经元亚群)会诱导盐水处理的 WT 和 KO 小鼠出现抑郁样行为,但不会诱导 LPS 处理的 KO 小鼠出现抑郁样行为。与 LPS 处理的 WT 小鼠的低兴奋性 mPFCGlu 神经元相比,C3aR 缺失的 mPFCGlu 神经元在 LPS 处理后表现出高兴奋性,而 mPFCGlu 神经元的兴奋增强具有抗抑郁作用,这表明在这些情况下 C3aR 的缺乏具有保护作用。总之,C3aR通过mPFCGlu神经元的兴奋性调节对LPS诱导的抑郁样行为的易感性。这项研究发现,C3aR是补体激活、mPFC功能障碍和抑郁的关键交叉点,也是治疗MDD的一个有希望的靶点。
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来源期刊
Progress in Neurobiology
Progress in Neurobiology 医学-神经科学
CiteScore
12.80
自引率
1.50%
发文量
107
审稿时长
33 days
期刊介绍: Progress in Neurobiology is an international journal that publishes groundbreaking original research, comprehensive review articles and opinion pieces written by leading researchers. The journal welcomes contributions from the broad field of neuroscience that apply neurophysiological, biochemical, pharmacological, molecular biological, anatomical, computational and behavioral analyses to problems of molecular, cellular, developmental, systems, and clinical neuroscience.
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