Serotonin Depletion Hampers Survival and Proliferation in Neurospheres Derived from Adult Neural Stem Cells

Abstract

Serotonin (5-HT) and the serotonergic system have recently been indicated as modulators of adult hippocampal neurogenesis. In this study, we evaluated the role of 5-HT on the functional features in neurospheres derived from adult neural stem cells (ANSC). We cultured neurospheres derived from mouse hippocampus in serum-free medium containing epidermal (EGF) and type-2 fibroblast growth factor (FGF2). Under these conditions ANSC expressed both isoforms of tryptophane-hydroxylase (TPH) and produced 5-HT. Blocking TPH function by para-chlorophenylalanine (PCPA) reduced ANSC proliferation, which was rescued by exogenous 5-HT. 5-HT action on ANSC was mediated predominantly by the serotonin receptor subtype 5-HT1A and, to a lesser extent, through the 5-HT2C (receptor) subtype, as shown by selectively antagonizing these receptors. Finally, we documented a 5-HT-induced increase of ANSC migration activity. In summary, we demonstrated a powerful serotonergic impact on ANSC functional features, which was mainly mediated by 5-HT1A receptors.

The role of serotonin in adult hippocampal neurogenesis

“…Under proliferation conditions, neural stem cells produce both, TPH and serotonin, and express 5-HT1A receptors (Benninghoff et al, 2010, Klempin et al, 2010. Self-renewal and proliferation is decreased by 5-HT1A blockage or PCPA treatment that is rescued by exogenous serotonin.…”

Serotonin-1A receptor binding is positively associated with gray matter volume — A multimodal neuroimaging study combining PET and structural MRI

“…Structural neuroimaging techniques revealed increased amounts of gray matter volume (GMV) as surrogate for enhanced neuroplasticity in relation to motoric training, cognitive performance or treatment with the antidepressant fluoxetine, a selective serotonin reuptake inhibitor (Draganski et al, 2004;Kanai and Rees, 2011;Vetencourt et al, 2008). On the other side, GMV loss as measured with highresolution structural magnetic resonance imaging (MRI), is a key feature of neuropsychiatric brain disorders, whereby the hippocampal formation was demonstrated to be especially vulnerable to volumetric alterations (Benninghoff et al, 2010;Geuze et al, 2005).…”

Lithium augmentation of the effects of desipramine in a mouse model of treatment-resistant depression: A role for hippocampal cell proliferation

“…Adult hippocampal cell proliferation can be regulated by serotonin (Benninghoff et al, 2010) and since lithiuminduced increases in serotonin have been reported (see above), the effects observed in the present study may be a result of increased serotonin in the hippocampus. Another possible candidate is glycogen synthase kinase 3 (GSK3), a constitutively active serine/threonine protein kinase that is inhibited by phosphorylation at serine-9 in its beta isoform, or serine-21 in its alpha isoform.…”