Date of Award

Spring 1-1-2012

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

First Advisor

Kevin Jones

Second Advisor

Michael Klymkowsky

Third Advisor

Min Han

Fourth Advisor

Harald Junge

Fifth Advisor

Chris Link

Abstract

Dendritic spines are major sites of excitatory synaptic transmission and changes in their densities and morphologies have been linked to neurodevelopmental disorders and neurodegenerative diseases. The Jones lab has previously shown using a forebrain-specific BDNF knockout mouse (fsBDNF-KO) that loss of BDNF leads to a significant reduction in dendritic spine density and a loss of dendrites in cortical neurons. However, the mechanisms by which BDNF regulates dendrites and dendritic spine formation remain unclear. I propose that one mechanism by which BDNF regulates these processes is by controlling the expression of other secreted signaling proteins, thereby establishing bidirectional communication between neurons. Global transcriptional analysis of fsBDNF-KO mice revealed that several Wnt genes are dysregulated along with other components of Wnt signaling pathways. The Wnts are a large family of secreted signaling proteins known to be regulated by neural activity and to regulate synapse function. However, a role for the Wnts in BDNF-mediated synapse formation in the CNS has not yet been described. Here, I demonstrate that blocking Wnt signaling in cortical neurons in vitro using four different Wnt signaling inhibitors impairs cortical dendrite growth and dendritic spine formation. Additionally, I show that Wnt signaling is required for both BDNF-induced dendritic spine formation and BDNF-induced changes in dendritic spine morphology associated with dendritic spine maturation. Further, I show that BDNF increases the expression of an individual Wnt gene, Wnt2, and may decrease the expression of another Wnt gene, Wnt4. Lastly, I demonstrate that Wnt2 is sufficient to increase dendrite growth, increase dendritic spine density and promote dendritic spine maturation, while Wnt4 is sufficient to increase dendritic spine density. Together, these data suggest that BDNF and Wnt signaling may cooperatively regulate dendritic spine formation and that BDNF may regulate dendritic spine formation in part by regulating expression of different Wnt genes.

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