We identified CaMKII as a downstream target of

We identified CaMKII as a downstream target of NMDA receptors activated in NPCs following TLQP-62 treatment. CaMKII can associate with NMDA receptors and ultimately sustain its activation state (Bayer et al., 2001). Supporting our novel findings for a role of CaMKII in neurogenesis is a study showing that mouse mutants for CaMKII have impairments in maturation of granule LDC000067 cost in the dentate gyrus (Yamasaki et al., 2008). A recent study demonstrates that olfactory bulbectomized mice treated with a steroid receptor agonist that activates CaMKII have increased neurogenesis as well as LTP (Moriguchi et al., 2013). The mechanism by which CaMKII induces TLQP-62-mediated proliferation following NMDA receptor activation has yet to be explored. Recently, two receptors for TLQP-21 have been described (Chen et al., 2013; Hannedouche et al., 2013). Both of these receptors C3aR1 and gC1qR are complement receptors and are thought to be involved in the role of TLQP-21 in neuropathic pain (Chen et al., 2013) and metabolism (Hannedouche et al., 2013). It has not yet been tested whether TLQP-62 binds to either of these receptors or whether they are expressed in the hippocampus. In this study, we explored the possible interactions between TLQP-62 with glutamate receptors as well as the BDNF receptor to yield novel insights into the signaling pathways of TLQP-62. We found that TLQP-62 requires activation of Trk receptors to mediate its effect on neurogenesis. Moreover, TLQP-62 induces phosphorylation of TrkB, albeit with a slower time course and to a lesser extent than BDNF. This suggests that TLQP-62 may not activate TrkB directly, but is perhaps inducing the release of BDNF, which in turn is binding to its receptor TrkB and promoting glutamate release. Alternatively, TLQP-62 could transactivate TrkB independently of BDNF as previously shown for adenosine and PACAP (pituitary adenylate cyclase-activating polypeptide) (Lee and Chao, 2001; Lee et al., 2002a,b). Our findings are supported by a previous study, which suggests that TrkB may be downstream of the effect of TLQP-62 on synaptic activity. Specifically, the transient potentiation of activity by TLQP-62 peptide could be blocked by the BDNF scavenger TrkB-Fc, the Trk tyrosine kinase inhibitor K252a and the tPA inhibitor tPA STOP (Bozdagi et al., 2008). The role of BDNF and its receptor TrkB in neurogenesis has been explored. Overexpression or infusion of BDNF in the adult rat results in newly generated cells (Benraiss et al., 2001; Pencea et al., 2001; Scharfman et al., 2005) and BDNF is required for enhancement of hippocampal neurogenesis (Lee et al., 2002a,b; Rossi et al., 2006). Although some studies suggest that BDNF promotes the survival rather than proliferation or differentiation of new neurons (Bath et al., 2008; Sairanen et al., 2005), TrkB deletion specifically in progenitor cells of the dentate gyrus results in impaired neurogenesis induced by antidepressant treatment, suggesting that proliferation of progenitor cells is mediated by TrkB signaling. Deletion of TrkB in differentiated cells of the dentate gyrus, on the other hand, had no effect on the number of neurons (Li et al., 2008). A possible explanation as to why some studies have found that BDNF affects proliferation (Li et al., 2008) while others have found it to only affect survival (Sairanen et al., 2005) is the use of different promoters to delete TrkB affected different cell populations (Banasr and Duman, 2008). Our studies suggest that TrkB may be playing a role in TLQP-62-induced proliferation of NPCs. We have previously shown that TLQP-62 expression is induced by factors that have antidepressant activity. Conversely, VGF is downregulated in rodent models of depression (Thakker-Varia et al., 2007). Along with others, we have demonstrated that infusion of VGF-derived peptides in the hippocampus of mice results in antidepressant-like outcomes (Hunsberger et al., 2007; Thakker-Varia et al., 2010). We have also shown that VGF is downregulated in human bipolar disorder and acts as a mood stabilizer in models of mania. Moreover, VGF levels are downregulated in leukocytes of depressed patients but are restored in response to antidepressant treatment (Cattaneo et al., 2010). BDNF has also been implicated in depression (Castren et al., 2007; Duman and Monteggia, 2006). Antidepressant agents activate TrkB (Rantamaki et al., 2007) and local infusion of BDNF or overexpression of TrkB receptor in the brain mimics antidepressant effects in animal models (Koponen et al., 2005; Shirayama et al., 2002; Siuciak et al., 1997). On the other hand, BDNF signaling is essential for the behavioral effects of the drugs (Monteggia et al., 2004; Saarelainen et al., 2003). Thus, decreased levels of VGF and BDNF contribute to depression and increased levels via antidepressant treatment result in enhanced neurogenesis in the hippocampus. Our data showing activation of TrkB by VGF-derived peptide TLQP-62 support a possible link between neuropeptides and neurotrophins in antidepressant actions.