All ETDs from UAB

Advisory Committee Chair

Richard S Jope

Advisory Committee Members

Gautam Bijur

Gail V W Johnson

Kevin A Roth

Rosa Serra

Document Type

Dissertation

Date of Award

2009

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Neurogenesis is a crucial process for development, plasticity, and regenerative capacity of the developing and adult brain. Impairment of neurogenesis has been implicated in the etiology of psychiatric disorders. Although substantial studies have shown that therapeutic interventions enhance neurogenesis, much less is known about what factors impair neurogenesis. Thus, the present work examined if glycogen synthase kinase-3 (GSK3) has a role in impaired neurogenesis, focusing on apoptosis and proliferation of neural precursor cells (NPCs). This investigation found that GSK3 promotes apoptotic signaling in cultured NPCs subjected to two insults, trophic factor withdrawal and genotoxic stress. Both stimuli activated GSK3, Bax, and caspase-3. Pharmacological inhibition of GSK3 activity reduced Bax and caspase-3 activation in both bax+/+ and bax-/- NPCs. GSK3β interacted with p53 after DNA damage in NPCs. This study also investigated the role of hyperactive GSK3 on NPC proliferation in the adult hippocampus using homozygous S21A/S9A-GSK3α/β knockin mice. In vivo measurements of BrdU positive cells showed a drastic 40 % impairment of proliferation in GSK3 knockin mice. Impaired neurogenesis observed in vivo was not due to direct effects of hyperactive GSK3 in NPCs because proliferation in vitro was equivalent in NPCs from both GSK3 knockin and wild-type mice, suggesting in vivo deficiency in GSK3 knockin mice of an external promoter of NPC proliferation. Measurements of two ii neurotrophins demonstrated less vascular endothelial growth factor, but not brain-derived neurotrophic factor, in the hippocampus of GSK3 knockin mice than wild-type mice, suggesting insufficient support molecules in vivo in GSK3 knockin mice impairs neurogenesis. Chronic administration of lithium and fluoxetine, which increase inhibitory serine-phosphorylation of wild-type GSK3, increased NPC proliferation in wild-type, but not GSK3 knockin, mice. Overall, this study reveals that GSK3 may be a crucial modulator of apoptosis and proliferation of NPCs. NPCs are sensitive to loss of trophic factors and genotoxic stress, and GSK3 inhibitors are capable of enhancing NPC survival. Blocked inhibitory control of GSK3 impairs NPC proliferation in the adult hippocampus and the capacity of therapeutic drugs to stimulate neurogenesis, likely through deficient environmental factors that support neurogenesis, which may contribute to psychiatric diseases and responses to therapeutic drugs.

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