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    • The effects of TLQP on neurogenesis

    2018-11-12

    The effects of TLQP-62 on neurogenesis are thus similar to what is reported for antidepressant fluoxetine and serotonin (5-HT), both of which increase the proportion of undetermined Type 2a NPCs marked by Nestin+ and DCX-immunostaining and lacking the radial glial-like morphology (Boku et al., 2011; Encinas et al., 2006). The effect of TLQP-62 is also similar to the effect of exercise, which stimulates the division of both Type 2a and Type 2b purchase A-1210477 (Kronenberg et al., 2003; Steiner et al., 2008). These findings support our theory that VGF-derived peptides affect a specific neurogenesis pathway and act as antidepressant-like agents (Hunsberger et al., 2007; Thakker-Varia et al., 2010) since both fluoxetine and exercise promote neurogenesis and have antidepressant-like actions (Engesser-Cesar et al., 2007; Huang et al., 2012). In contrast, kainic acid, a compound that induces seizures and subsequently results in aberrant neurogenesis, but does not have antidepressant-like activity, is known to promote Type 3 (determined migratory) NPCs over the earlier stages in its differentiation pathway (Jessberger et al., 2005; Steiner et al., 2008). Thus, our results suggest that VGF-derived peptides, which are known to have antidepressant effects in animal models (Hunsberger et al., 2007; Thakker-Varia et al., 2007, 2010), have a similar mechanism in promoting neurogenesis as “classical” antidepressants. In this study, the mechanism of TLQP-62-induced proliferation was dissected using NPCs in vitro. We detected equivalent increased proliferation of NPCs by TLQP-62 on both coated plates as well as a bed of hippocampal cultures suggesting that the effect of TLQP-62 on NPC proliferation is cell autonomous and does not require factors provided by other cells in the hippocampus. In contrast, there was no significant effect of TLQP-62 on differentiation of NPCs on either type of substrate, consistent with the in vivo data that TLQP-62 promotes early phases of neurogenesis rather than differentiation and indicating that non-cell autonomous factors are not sufficient to induce differentiation by TLQP-62. The positive control, KCl, was expected to significantly enhance differentiation relative to the untreated controls (Deisseroth et al., 2004), which it only did on the polyornithine plus laminin coated dishes. It is believed that KCl failed to enhance differentiation when NPCs were plated on a bed of hippocampal neurons in our study because the prolonged exposure to KCl could have had excitotoxic effects on the mature hippocampal neurons which in turn may have affected the health of the NPCs. To further delineate the role of TLQP-62 in proliferation, we examined the cell cycle status of the cells treated with the neuropeptide. D-type cyclins control the transition from G1 to S (Sherr, 1994). D-type cyclins are thought to be a molecular link between the extracellular environment and the cell cycle machinery since they are synthesized in response to mitogens and their expression rapidly declines when mitogens are withdrawn (Matsushime et al., 1994). D-type cyclins have been shown to be regulated by other neuropeptides that affect proliferation in normal as well as neoplastic cells in the body (de Mendonca et al., 2013; Fernandez-Martinez et al., 2009; Song et al., 2003). In the nervous system, neuropeptides such as pituitary adenylate cyclase-activating polypeptide (PACAP) and extracellular signaling molecule, Wnt7a stimulate Cyclin D expression and regulate cerebral cortical proliferation (Qu et al., 2013; Yan et al., 2013). Moreover, Cyclin D2 knockout mice have impaired adult hippocampal neurogenesis (Ansorg et al., 2012; Kowalczyk et al., 2004) whereas overexpression of Cyclin D1 causes an expansion of the neural progenitor cells in the adult mouse hippocampus (Artegiani et al., 2011). Our data demonstrate that cyclin D1 and D2 mRNA levels are upregulated in response to TLQP-62 treatment of NPCs but that scrambled control peptide PEHN-62 has no effect on cyclin D expression. Thus one mechanism by which TLQP-62 regulates neurogenesis may be by altering the expression of proteins which control the cell cycle machinery.