Stem cell self-renewal is a consequence of the ability to proliferate indefinitely while maintaining pluripotency. In the adult brain, neural stem cells continuously produce neurons, and its importance for memory and repair after neurodegeneration and brain damage has been extensively investigated. However, adult neurogenesis is limited and significantly decreases throughout life. With aging, increased senescence greatly restrains the neurogenic potential of aged stem cells. Senescence induction is critically controlled by the INK4a/Arf locus, but the mechanisms of senescence induction are largely unknown. It is essential to understand the mechanisms involved in the control of stem cell proliferation and senescence for the development of stem cell-based therapies. The host laboratory identified that embryonic and peripheral neural stem cell proliferation is regulated by a novel mechanism that involves S-phase cell cycle arrest, GABA signaling and the histone variant H2AX (Andäng et al Nature 2008). This proposal aims to investigate whether GABAAR and H2AX-mediated modulation of stem cell proliferation is a factor in age-related decline in neurogenesis, and if this pathway could be modulated towards boosting neurogenesis following neurodegeneration or damage. H2AX is also involved in senescence, being activated following telomere erosion. We propose to investigate the mechanisms of senescence induction and the interaction between critical regulators of cell cycle. This will provide new information on the conserved and unique pathways involved in the control of stem cell proliferation and senescence. The investigation of the mechanisms involved in age-related neurogenic decline and how neurogenesis can be boosted may open the way for new clinically relevant strategies increasing self-repair following brain damage and neurodegeneration.