PDGF-BB依赖性神经发生通过抑制从内侧隔膜到齿状回的GABA能投射来缓冲抑郁样行为,Advanced Science

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PDGF-BB依赖性神经发生通过抑制从内侧隔膜到齿状回的GABA能投射来缓冲抑郁样行为
Advanced Science ( IF 14.3 ) Pub Date : 2023-06-16 , DOI: 10.1002/advs.202301110
Hou-Hong Li ₁ , Yang Liu ₁ , Hong-Sheng Chen _{1,

2} , Ji Wang ₁ , Yu-Ke Li ₁ , Yang Zhao ₁ , Rui Sun ₁ , Jin-Gang He _{1,

2,

3,

4} , Fang Wang _{1,

2,

3,

4} , Jian-Guo Chen _{1,

2,

3,

4}

Affiliation

海马回路刺激足以调节成人海马神经发生并改善抑郁样行为，但其潜在机制仍不清楚。在这里，研究表明，抑制内侧隔（MS）-齿状回（DG）回路可以逆转慢性社交失败压力（CSDS）引起的抑郁样行为。进一步分析表明，抑制 MS 中投射到 DG 的 γ-氨基丁酸能神经元 (MS ^GABA+ -DG) 会增加 DG 生长抑素 (SOM) 阳性中间神经元中血小板衍生生长因子-BB (PDGF-BB) 的表达，有助于抗抑郁样作用。DG 中 PDGF-BB 的过度表达或外源性施用 PDGF-BB 可挽救慢性应激对神经干细胞 (NSC) 增殖和成年海马神经元树突生长的抑制以及抑郁样行为的影响。相反，PDGF-BB 的敲低会促进 CSDS 诱导的海马神经发生缺陷，并增加小鼠对慢性应激的易感性。最后，有条件地敲低 NSC 中的血小板衍生生长因子受体 β (PDGFR β ) 可阻止 NSC 增殖的增加和 PDGF-BB 的抗抑郁作用。这些结果描绘了先前未识别的 PDGF-BB/PDGFR β信号传导在调节抑郁样行为中的作用，并确定了 MS ^GABA+ -DG 通路调节 SOM 阳性中间神经元中 PDGF-BB 表达的新机制。

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PDGF-BB-Dependent Neurogenesis Buffers Depressive-Like Behaviors by Inhibition of GABAergic Projection from Medial Septum to Dentate Gyrus

Hippocampal circuitry stimulation is sufficient to regulate adult hippocampal neurogenesis and ameliorate depressive-like behavior, but its underlying mechanism remains unclear. Here, it is shown that inhibition of medial septum (MS)-dentate gyrus (DG) circuit reverses the chronic social defeat stress (CSDS)-induced depression-like behavior. Further analysis exhibits that inhibition of gamma-aminobutyric acidergic neurons in MS projecting to the DG (MS^GABA+-DG) increases the expression of platelet-derived growth factor-BB (PDGF-BB) in somatostatin (SOM) positive interneurons of DG, which contributes to the antidepressant-like effects. Overexpression of the PDGF-BB or exogenous administration of PDGF-BB in DG rescues the effect of chronic stress on the inhibition of neural stem cells (NSCs) proliferation and dendritic growth of adult-born hippocampal neurons, as well as on depressive-like behaviors. Conversely, knockdown of PDGF-BB facilitates CSDS-induced deficit of hippocampal neurogenesis and promotes the susceptibility to chronic stress in mice. Finally, conditional knockdown platelet-derived growth factor receptor beta (PDGFRβ) in NSCs blocks an increase in NSCs proliferation and the antidepressant effects of PDGF-BB. These results delineate a previously unidentified PDGF-BB/PDGFRβ signaling in regulating depressive-like behaviors and identify a novel mechanism by which the MS^GABA+-DG pathway regulates the expression of PDGF-BB in SOM-positive interneurons.

更新日期：2023-06-16

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