PDGF-BB-Dependent Neurogenesis Buffers Depressive-Like Behaviors by Inhibition of GABAergic Projection from Medial Septum to Dentate Gyrus.
PDGF-BB-Dependent Neurogenesis Buffers Depressive-Like Behaviors by Inhibition of GABAergic Projection from Medial Septum to Dentate Gyrus.
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DOI：
10.1002/advs.202301110
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发表时间：
2023-08
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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，但其潜在机制尚不清楚。本研究表明，抑制内侧隔(MS) -齿状回（DG）回路可逆转慢性社会失败应激（CSDS）诱导的抑郁样行为。进一步的分析表明，抑制MS中投射到DG的γ -氨基丁酸能神经元（MSGABA+‐DG）增加了DG中生长抑素（SOM）阳性中间神经元中血小板衍生生长因子‐BB （PDGF‐BB）的表达，这有助于抗抑郁样作用。在DG中过度表达PDGF - BB或外源性给药PDGF - BB可以缓解慢性应激对神经干细胞（NSCs）增殖和成体海马神经元树突状生长的抑制作用，以及对抑郁样行为的影响。相反，PDGF - BB的下调促进了CSDS诱导的海马神经发生缺陷，并促进了小鼠对慢性应激的易感性。最后，有条件地敲低NSCs中的血小板衍生生长因子受体β (PDGFRβ)可阻断NSCs增殖的增加和PDGF - BB的抗抑郁作用。这些结果描述了先前未知的PDGF - BB/PDGFRβ信号在调节抑郁样行为中的作用，并确定了MSGABA+ - DG通路调节SOM阳性中间神经元中PDGF - BB表达的新机制。该研究描述了MSGABA+‐DG电路和新型下游分子PDGF‐BB的功能连接。抑制MSGABA+ - DG通路增加了SOM阳性中间神经元中PDGF - BB的表达，这能够通过激活Janus激酶信号转导器2和转录激活器3 （JAK2/STAT3）信号通路，以PDGF - β依赖的方式增强成人海马神经发生，从而改善慢性应激诱导的抑郁样行为。
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 (MSGABA+‐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 MSGABA+‐DG pathway regulates the expression of PDGF‐BB in SOM‐positive interneurons. The study describes the functional connectivity in the MSGABA+‐DG circuit and the novel downstream molecule PDGF‐BB. Inhibition of MSGABA+‐DG pathway increases the expression of PDGF‐BB in SOM‐positive interneurons, which is capable of enhancing adult hippocampal neurogenesis in a PDGFRβ‐dependent manner by activating the Janus kinase‐signal transducer 2 and activator of transcription 3 (JAK2/STAT3) signaling pathway, leading to the improvement of chronic stress‐induced depressive‐like behavior.