SGZ adult neurogenesis is regulated by Diazepam Binding Inhibitor

Adult neurogenesis adds an entirely new level of plasticity to the brain and raises hope to use stem cell therapy to repair damaged nervous tissue. To understand the role of neurogenesis in the adult brain and to harness its potential it is of utmost importance to understand the regulation of the stem cell niches. Our group previously showed that the endozepine DBI is expressed in neuronal progenitors in the SVZ and that it reduces GABA signalling in these cells. Via this mechanism, DBI promotes the proliferation of fast dividing progenitors which leads to a strong increase in neurogenesis. Here I investigated the presence of DBI in other neurogenic niches and its role in regulating postnatal and adult neurogenesis. I found that DBI is strongly expressed in the SGZ and in the walls of the 3rd ventricle both postnatally and in adult mice. Furthermore, I showed that DBI is present in RG cells during embryonic development. I found that DBI is expressed not only in all mouse postnatal and adult neurogenic niches but also across species in the SGZ of the Rhesus monkey and in humans. High expression levels of DBI were detected in all stem cells and in the early population of amplifying progenitors, suggesting that this protein could be considered as an indicator for stemness in the nervous tissue. Focusing on the SGZ, I showed that DBI negatively modulates the activity of the GABAA receptor in stem cells, thereby increasing their proliferation, self-renewal and astrocyte production. In summary, DBI together with GABA regulate the balance between preserving the stem cell pool and neuronal production. External factors such as environmental enrichment and physical exercise strongly enhance neurogenesis. I found in this study that DBI is essential for the pro-proliferative and pro-neurogenic effects of enriched environment and exercise. Therefore, DBI and GABA regulate SGZ neurogenesis in a close partnership enabling multiple levels of control which makes the niche dynamic and capable of reacting promptly to changes in the environment