Paradoxical increase in survival of newborn neurons in the dentate gyrus of mice with constitutive depletion of serotonin

DIAZ SL

Thessaloniki

Congreso; FENS Features Regional Meeting; 2015

Federation of European Neurosciences Societies

The reestablishment of serotonergic neurotransmission has been classically related to the therapeutic effects of selective serotonin reuptake inhibitors (SSRI) antidepressants. Later, since the first study showing an enhancement of adult-born neurons in the hippocampus of rats chronically treated with SSRIs (Malberg et al., 2000) it was generally accepted that some behavioural effects induced by antidepressants require enhanced hippocampal neurogenesis. These effects were supposed to be mediated by an increase of serotonergic transmission, as this is the main effect of SSRIs. These findings lead to the prediction that a decrease in serotonin levels would determine a decline in hippocampal adult neurogenesis. We challenged this hypothesis by demonstrating a counterintuitive increase of hippocampal cell survival in three different mice models with profound reductions of serotonin neurotransmission. Indeed, mutant mice with lifelong depletion of brain serotonin and mice with pharmacological inhibition of serotonin synthesis during adulthood displayed normal levels of hippocampal cell proliferation but enhanced cell survival in the dentate gyrus.Our observations were replicated in another model of hyposerotonergy (Sachs et al, Transl Psy 2013), supporting the concept that physiological levels of serotonin are essential for normal survival of adult-born-neurons. Moreover, Klempin et al. (2013), showed that no extra proneurogenic effect can be induced by exercise in hyposerotonergic mice, adding evidence to the hypothesis of decreased plasticity as a consequence of a saturated neurogenic process.We further explored the role of the serotonin system on physiological neurogenesis, and found that stimulation of the 5-HT1A receptors is sufficient to normalize the altered survival phenotype reported in serotonin-depleted mice. The 5-HT1A receptors are expressed by neural progenitors and GABAergic interneurons in the hippocampus (Klemplin et al., 2010). Particularly, parvalbumin-expressing GABAergic interneurons participate in the differentiation and maturation of progenitor cells in the dentate gyrus through BDNF, appearing as attractive targets to unravel the exact role of serotonin pathways on the fate of adult-born hippocampal neurons.All in all, this article opened a series of exciting questions to explore and better understand the pathways and mechanisms underlying hippocampal adult neurogenesis.