Journal Article

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

Almudena Fuster-Matanzo, María Llorens-Martín, María Salomé Sirerol-Piquer, José Manuel García-Verdugo, Jesús Avila and Félix Hernández

in Human Molecular Genetics

Volume 22, issue 7, pages 1300-1315
Published in print April 2013 | ISSN: 0964-6906
Published online December 2012 | e-ISSN: 1460-2083 | DOI: https://dx.doi.org/10.1093/hmg/dds533
Dual effects of increased glycogen synthase kinase-3β activity on adult neurogenesis

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Adult neurogenesis, the generation of new neurons during the adulthood, is a process controlled by several kinases and phosphatases among which GSK3β exerts important functions. This protein is particularly abundant in the central nervous system, and its activity deregulation is believed to play a key role in chronic disorders such as Alzheimer's disease. Previously, we reported that in vivo overexpression of GSK3β (Tet/GSK3β 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 environment, 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 increasing GSK3 activity are susceptible to revert after doxycycline treatment. We show that transgene shutdown 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/GSK3β mice could not be reverted. Thus, alterations 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.

Journal Article.  9000 words.  Illustrated.

Subjects: Genetics and Genomics

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