Thakker-Varia Smita, Behnke Joseph, Doobin David, Dalal Vidhi, Thakkar Keya, Khadim Farah, Wilson Elizabeth, Palmieri Alicia, Antila Hanna, Rantamaki Tomi, Alder Janet
Department of Neuroscience and Cell Biology, Rutgers University - Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA.
Neuroscience Center, University of Helsinki, P.O. Box 56, Viikinkaari 4, 00014 Helsinki, Finland.
Stem Cell Res. 2014 May;12(3):762-77. doi: 10.1016/j.scr.2014.03.005. Epub 2014 Mar 26.
The neuropeptide VGF (non-acronymic), which has antidepressant-like effects, enhances adult hippocampal neurogenesis as well as synaptic activity and plasticity in the hippocampus, however the interaction between these processes and the mechanism underlying this regulation remain unclear. In this study, we demonstrate that VGF-derived peptide TLQP-62 specifically enhances the generation of early progenitor cells in nestin-GFP mice. Specifically, TLQP-62 significantly increases the number of Type 2a neural progenitor cells (NPCs) while reducing the number of more differentiated Type 3 cells. The effect of TLQP-62 on proliferation rather than differentiation was confirmed using NPCs in vitro; TLQP-62 but not scrambled peptide PEHN-62 increases proliferation in a cell line as well as in primary progenitors from adult hippocampus. Moreover, TLQP-62 but not scrambled peptide increases Cyclin D mRNA expression. The proliferation of NPCs induced by TLQP-62 requires synaptic activity, in particular through NMDA and metabotropic glutamate receptors. The activation of glutamate receptors by TLQP-62 activation induces phosphorylation of CaMKII through NMDA receptors and protein kinase D through metabotropic glutamate receptor 5 (mGluR5). Furthermore, pharmacological antagonists to CaMKII and PKD inhibit TLQP-62-induced proliferation of NPCs indicating that these signaling molecules downstream of glutamate receptors are essential for the actions of TLQP-62 on neurogenesis. We also show that TLQP-62 gradually activates Brain-Derived Neurotrophic Factor (BDNF)-receptor TrkB in vitro and that Trk signaling is required for TLQP-62-induced proliferation of NPCs. Understanding the precise molecular mechanism of how TLQP-62 influences neurogenesis may reveal mechanisms by which VGF-derived peptides act as antidepressant-like agents.
具有类抗抑郁作用的神经肽VGF（无首字母缩写）可增强成年海马神经发生以及海马中的突触活性和可塑性，然而这些过程之间的相互作用以及这种调节的潜在机制仍不清楚。在本研究中，我们证明VGF衍生肽TLQP-62可特异性增强巢蛋白绿色荧光蛋白（nestin-GFP）小鼠早期祖细胞的生成。具体而言，TLQP-62显著增加2a型神经祖细胞（NPC）的数量，同时减少分化程度更高的3型细胞的数量。使用体外培养的NPC证实了TLQP-62对增殖而非分化的影响；TLQP-62而非乱序肽PEHN-62可增加细胞系以及成年海马原代祖细胞的增殖。此外，TLQP-62而非乱序肽可增加细胞周期蛋白D（Cyclin D）mRNA的表达。TLQP-62诱导的NPC增殖需要突触活性，特别是通过N-甲基-D-天冬氨酸（NMDA）和代谢型谷氨酸受体。TLQP-62激活谷氨酸受体可通过NMDA受体诱导钙/钙调蛋白依赖蛋白激酶II（CaMKII）磷酸化，并通过代谢型谷氨酸受体5（mGluR5）诱导蛋白激酶D（PKD）磷酸化。此外，CaMKII和PKD的药理学拮抗剂可抑制TLQP-62诱导的NPC增殖，表明谷氨酸受体下游的这些信号分子对于TLQP-62对神经发生的作用至关重要。我们还表明，TLQP-62在体外可逐渐激活脑源性神经营养因子（BDNF）受体酪氨酸激酶B（TrkB），并且Trk信号传导是TLQP-62诱导的NPC增殖所必需的。了解TLQP-62影响神经发生的精确分子机制可能揭示VGF衍生肽作为类抗抑郁剂发挥作用的机制。
