Adult hippocampal neural progenitor cells: an Important In vitro tool for studying complex mechanisms regulating adult neurogenesis

Adult hippocampal neurogenesis (ahNG) is a peculiar form of neural plasticity involved in crucial brain functions including cognition, mood and stress response. Adult hippocampal neural progenitor cells (ahNPC) differentiation is modulated positively or negatively by several factors. Understanding the mechanisms regulating ahNG will shed light on its role in brain physiopathology. Astrocytes, one of the major component of the neurogenic niche, might regulate ahNPC fate specification. Little is known about the identity of astrocytes-secreted proteins and the subcellular mechanisms mediating their modulatory effect. Interestingly ahNG is deregulated in neuropsychiatric disorders such as major depression. The specific involvement of serotonin (5-HT) receptors family in mediating antidepressants (AD) effect add more complication into serotonin role in depression and is still not extensively described. Several studies documented a role of NF-B signaling in ahNPC response to proneurogenic molecules. Yet scarce data described how the knockout of NF-B p50 subunit (p50KO) could affect ahNG. In vitro analysis of astrocytes conditioned media (ACM) effect on ahNPC differentiation, showed that p50 absence induced intrinsic and extrinsic defects in both cell types. These results could explain earlier study published in our group showing that p50KO mice have reduced ahNG and severe deficits in hippocampal-dependent cognitive performance. Moreover, lipocalin-2 (LCN-2) was identified as a novel astrocyte-derived proneurogenic signal. In the second part of the study we showed that 5-HT2A/2C receptors antagonism and 5-HT7 activation are proneurogenic on ahNPC. Moreover NF-B p50 subunit presence was required for the multimodal AD induced increase of neurogenesis. In conclusion, ahNPC modulation by astrocyte-released factors and serotonin receptors might be future pharmacological targets for increasing ahNG specifically in neurodegenerative and neuropsychiatric disorders.