The indirect effect of taurine on adult neurogenesis may be
The indirect effect of taurine on adult neurogenesis may be mediated by its anti-inflammatory properties: taurine reduces the production of inflammatory cytokines such as TNFα or IL-1β (Kim & Cha, 2014) and its derivative, taurine-chloramine, reduces the activation of NFkb in several models of inflammation (Kim & Kim, 2005). In the brain, taurine administration reduces cell damage and cytokines expression after traumatic Recent data injury (Chan et al., 2014) and mitigates lipopolysaccharide-induced inflammation and microglia activation (Menzie et al., 2013). In physiological conditions, brain aging is accompanied by increased expression of genes involved in cellular stress and inflammation (Sturman et al., 1985) and increased microglia proliferation and activity (Kohman, 2012). In turn, this increased inflammation negatively correlates with hippocampal RGL stem cells proliferation (Gebara et al., 2013). Thus, the increased inflammation in the aging brain inhibits hippocampal neurogenesis and conversely, anti-inflammatory treatments that reduce microglia activation, increase adult neurogenesis (Gebara et al., 2013; Sultan et al., 2013b). Consistent with these observations, taurine partially restores cell proliferation in the DG after lipopolysaccharide-induced inflammation (Menzie et al., 2013). Altogether, these results suggest that the effect of taurine on adult neurogenesis that we observed in the aging brain may be, at least partially, mediated by a reduction in microglia activation. Although we did not directly measure levels of inflammatory cytokines in this study, this possibility is consistent with our observations of decreased microglia number, reduced morphological markers that are normally associated with activation and reduced MHC-II expression upon taurine treatment. In addition to its indirect effect, taurine directly increased the proliferation of purified adult hippocampal stem/progenitor cells in vitro, similarly to what was previously observed on subventricular zone progenitors (Ramos-Mandujano et al., 2014). The antioxidant (Schaffer et al., 2009) and antiapoptotic properties of taurine (Taupin, 2007; Sultan et al., 2013a), can potentially contribute to the increased proliferation and survival rate of the highly proliferative and metabolically active neural stem cells and new neurons. Of particular interest, taurine has recently been shown to interact with the polyamine site of the NMDA receptor and modulate the activity of the NMDA receptor (Chan et al., 2014). NMDA receptors are expressed by RGL stem cells and regulate their activity (Muth-Kohne et al., 2010), as demonstrated by the increased proliferation induced by the NMDA receptor antagonists memantine or MK-801 (Namba et al., 2009), and the co-agonist d-serine (Sultan et al., 2013a). NMDA receptors are also expressed on immature adult-born hippocampal neurons and are required for the survival of these cells (Tashiro et al., 2006). Thus, by directly modulating NMDA receptor activity on RGL stem cells and on immature neurons, taurine may increase the proliferation of the former and the survival of the latter and thereby contribute to the increased neurogenesis we observed. Endogenous taurine is released by astrocytes (Choe et al., 2012) and may contribute to the regulation of adult neurogenesis by the microenvironment. With age, the dysregulation of the neurogenic niche (Bernal & Peterson, 2011; Katsimpardi et al., 2014) may involve a reduction of astrocytic function, leading to reduced taurine production, thereby causing age-related impaired neurogenesis. Reduced adult neurogenesis contributes to age-related cognitive impairment and several therapeutic approaches for stroke or neurodegenerative disorders target adult neurogenesis. The renewal of stem cells in the adult brain being limited (Calzolari et al., 2015), approaches that increase the stem cell pool may yield a more promising outcome for restoring neurogenesis in the aged brain, than targeting later stages of the process. In light of our results, the potent activating effect of taurine on RGL stem cells may underlie its beneficial cognitive effects and may represent a promising approach for the treatment of age-related reduction in adult neurogenesis and cognition.