CREB-Dependent Regulation of Dendritic Morphology

Thesis (Ph.D.), Program in Neuroscience, Washington State UniversityA significant number of human developmental and psychiatric disorders are strongly correlated with abnormalities in the dendritic morphology of neurons. The dendritic arbor of a neuron, a set of tree branch-like projections, is the primary site for receiving neuronal signals, and the shape and size of the dendritic arbor is proportional to the number of synaptic connections the neuron has developed. Small protrusions from the dendrites, called dendritic spines, mark the location of synaptic terminals along the length of the dendrite. Although structural changes in in both the dendritic arbor and dendritic spines can occur over the course of minutes, long-term stability requires transcriptional regulation and protein synthesis. The activity of the transcription factor, cAMP response element-element binding protein (CREB), has been shown to be essential to the development of the dendritic arbor, and it regulates the expression of numerous genes that regulate dendritic growth and spine formation. CREB-dependent transcription is influenced by numerous cellular signals and signaling pathways. Here we identify four molecules that are up regulated by activation of CREB-dependent transcription by various stimuli in cultured hippocampal neurons, and that are necessary for dendritic spine formation. Our first study demonstrates that brain derived neurotrophic (BDNF)-induced increases in dendritic spines require the expression of Par6C and Rnd3 by CREB. In the second study we demonstrate an environmental neurotoxin, PCB95, stimulates an overdevelopment of dendritic spines, in part, by inducing CREB-dependent expression of micro-RNA 132. Lastly, BDNF requires the expression of the transcription factor, MafF, by CREB to induce dendritic spine formation. These studies demonstrate novel ways by which CREB-dependent transcription regulates neuronal morphology. Understanding the precise mechanisms regulating CREB-dependent dendritic growth and dendritic spine formation (spinogenesis) can provide a strong foundation for developing therapies to treat many developmental and psychiatric disorders.Program in Neuroscience, Washington State Universit