Adult hippocampal neurogenesis in the absence of serotonin (Commentary on Diaz et al.).

Serotonergic neurotransmission is widely recognized to play a key role in hippocampal neurogenesis and in mediating antidepressant effects of selective serotonin reuptake inhibitors. These drugs not only increase the extracellular concentration of serotonin, they also enhance the production, structural complexity and survival of adult-born neurons in the hippocampus. Consistent with a role of serotonin in promoting neurogenesis, diverse environmental conditions that diminish adult neurogenesis (i.e. stress) also decrease the density of serotonergic axons or the release of serotonin. In addition, suppression of hippocampal neurogenesis abolishes many of the behavioral effects of antidepressants (reviewed in Samuels & Hen, 2011). However, the molecular mechanisms of action of antidepressants and serotonin in the control of hippocampal neurogenesis remain largely unresolved. The intuitive prediction that high levels of serotonin are beneficial to neurogenesis while decreased levels are detrimental is clearly too simplistic. Diaz et al. (2013, this issue) add a new and surprising twist to an evolving story of complex interactions. They challenge the notion that serotonin is required for normal levels of hippocampal neurogenesis, and that a lack of serotonin should lead to deficits in maturation and cell survival. Using two different mutant mouse strains designed to exhibit lifelong depletion of serotonin selectively in the brain, or more acute pharmacological blockade of serotonin synthesis in adulthood, they show that serotonin is dispensable for normal basal proliferation of hippocampal neural progenitors. Unaltered proliferation of adult-born neurons in the virtual absence of serotonin is consistent with a recent report by Klempin et al. (2013) who came to the same conclusion by analyses of tryptophan hydroxylase 2 knockout mice. However, this same report showed that serotonin is essential for chronic exercise-induced proliferation of progenitor cells. Moreover, chronic exercise has recently been shown to increase the salience of local c-aminobutyric acid (GABA)ergic inhibitory mechanisms and to reduce excitability of neural progenitor cells in the dentate gyrus (Schoenfeld et al., 2013). GABAergic interneurons in the vicinity of stem cells are also known to inhibit the mitotic activation and proliferation of these cells (Song et al., 2012). Therefore, serotonin-mediated inhibition of GABAergic interneurons can be predicted to promote progenitor proliferation by reducing GABAergic inhibition of quiescent stem cells and early neural progenitors in the stem cell niche. Most strikingly, Diaz et al. (2013) find that the survival of immature hippocampal neurons is substantially enhanced in the absence of serotonin, suggesting that serotonin normally delimits the survival of adult-born neurons. They further show that treatment of serotonin-depleted mice with the 5-HT1A agonist 8-OH-DPAT decreases cell survival to normal levels, suggesting that 5-HT1A receptor activity in the hippocampus promotes apoptosis of adult-born neurons. It is not yet clear to what extent the functionally relevant 5-HT1A receptors that promote apoptosis reside on neural progenitors or GABAergic interneurons. However, it is these latter cells that most prominently express the 5-HT1A receptor (Klempin et al., 2010). Moreover, it is well established that local interneuron-derived GABA acts via different subtypes of GABAA receptors not only to limit stem cell activation (Song et al., 2012), proliferation and post-mitotic migration of early progenitor cells (Duveau et al., 2011), but also to promote the maturation (Tozuka et al., 2005), survival (Earnheart et al., 2007) and synaptic integration (Ge et al., 2006) of granule cells. The work by Diaz et al. (2013) allows for speculation that direct and indirect hippocampal serotonergic pathways determine the balance between neural apoptosis and survival of adult-born neurons. We look forward to future experiments that will support or refute these predictions.