The neurotrophin-inducible gene Vgf regulates hippocampal function and behavior through a brain-derived neurotrophic factor-dependent mechanism.
The neurotrophin-inducible gene Vgf regulates hippocampal function and behavior through a brain-derived neurotrophic factor-dependent mechanism.
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DOI：
10.1523/jneurosci.3145-08.2008
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发表时间：
2008-09-24
期刊：
影响因子：
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通讯作者：
Salton SR
中科院分区：
文献类型：
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作者：
Bozdagi O;Rich E;Tronel S;Sadahiro M;Patterson K;Shapiro ML;Alberini CM;Huntley GW;Salton SR
VGF 是一种神经营养蛋白诱导的、活性调节的基因产物，在 CNS 和 PNS 神经元中表达，在神经元中被加工成肽并分泌。 VGF 合成受到 BDNF 的刺激，BDNF 是海马发育和功能的关键调节因子，并且两个 VGF C 末端肽可增加培养的海马神经元的突触活性。为了评估海马体中的 VGF 功能，我们在两种不同的学习任务中测试了杂合子和纯合子 VGF 敲除小鼠，评估了 VGF 突变小鼠海马切片的长时程增强 (LTP) 和抑制 (LTD)，并研究了 VGF C 端肽如何调节突触可塑性。用 VGF 衍生肽 TLQP62 处理大鼠海马切片，通过一种机制产生短暂的增强作用，该机制被 BDNF 清除剂 TrkB-Fc、Trk 酪氨酸激酶抑制剂 K252a (100 nM) 和 tPASTOP（组织纤溶酶原激活剂 (tPA) 的一种酶，参与 pro-BDNF 裂解为 BDNF，但不被 NMDA 受体拮抗剂 APV、抗 p75NTR 功能阻断抗血清或先前的破伤风刺激所阻断。尽管 VGF 敲除小鼠的切片中 LTP 正常，但无法诱导 LTD，并且 VGF 突变小鼠的海马依赖性空间学习和情境恐惧条件反射任务受到损害。我们的研究表明，VGF C 端肽 TLQP62 通过 BDNF 依赖性机制调节海马突触传递，并且小鼠中 VGF 缺乏除了影响抑郁行为外，还会影响突触可塑性和记忆。
VGF is a neurotrophin-inducible, activity-regulated gene product that is expressed in CNS and PNS neurons, where it is processed into peptides and secreted. VGF synthesis is stimulated by BDNF, a critical regulator of hippocampal development and function, and two VGF C-terminal peptides increase synaptic activity in cultured hippocampal neurons. To assess VGF function in the hippocampus, we tested heterozygous and homozygous VGF knockout mice in two different learning tasks, assessed long-term potentiation (LTP) and depression (LTD) in hippocampal slices from VGF mutant mice, and investigated how VGF C-terminal peptides modulate synaptic plasticity. Treatment of rat hippocampal slices with the VGF-derived peptide TLQP62 resulted in transient potentiation through a mechanism that was selectively blocked by the BDNF scavenger TrkB-Fc, the Trk tyrosine kinase inhibitor K252a (100 nM), and by tPASTOP, an inhibitor of tissue plasminogen activator (tPA), an enzyme involved in pro-BDNF cleavage to BDNF, but was not blocked by the NMDA receptor antagonist APV, anti-p75NTR function-blocking antiserum, nor by prior tetanic stimulation. Although LTP was normal in slices from VGF knockout mice, LTD could not be induced, and VGF mutant mice were impaired in hippocampal-dependent spatial learning and contextual fear conditioning tasks. Our studies indicate that the VGF C-terminal peptide TLQP62 modulates hippocampal synaptic transmission through a BDNF-dependent mechanism, and that VGF deficiency in mice impacts synaptic plasticity and memory in addition to depressive behavior.