Dual effects of increased glycogen synthase kinase-3b activity on adult neurogenesis

Adult neurogenesis, the generation of new neurons during the adulthood, is a process controlled by several kinases and phosphatases among which GSK3b exerts important functions. This protein is particularly abun-dant in the central nervous system, and its activity deregulation is believed to play a key role in chronic dis-orders such as Alzheimer’s disease. Previously, we reported that in vivo overexpression of GSK3b (Tet/ GSK3b mice) causes alterations in adult neurogenesis, leading to a depletion of the neurogenic niches. Here, we have further characterized those alterations, finding a delay in the switching-off of doublecortin marker as well as changes in the survival and death rates of immature precursors and a decrease in the total number of mature neurons. Besides, we have highlighted the importance of the inflammatory environ-ment, identifying eotaxin as a possible modulator of the detrimental effects on adult neurogenesis. Taking advantage of the conditional system, we have also explored whether these negative consequences of in-creasing GSK3 activity are susceptible to revert after doxycycline treatment. We show that transgene shut-down in symptomatic mice reverts microgliosis, abnormal eotaxin levels as well as the aforementioned alterations concerning immature neurons. Unexpectedly, the decrease in the number of mature neurons and neuronal precursor cells of the subgranular zone of Tet/GSK3b mice could not be reverted. Thus, altera-tions in adult neurogenesis and likely in neurodegenerative disorders can be restored in part, although neurogenic niche depletion represents a non-reversible damage persisting during lifetime with a remarkable impact in adult mature neurons