Thesis (Ph. D. in Neuroscience)--Massachusetts Institute of Technology, Dept. of Brain and Cognitive Sciences, February 2013.
This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.
Cataloged from student-submitted PDF version of thesis. "February 2013." Page 192 blank.
Includes bibliographical references.
The neuronal serine/threonine kinase cyclin-dependent kinase 5 (Cdk5) is activated by its regulatory subunit, p35, to post-translationally modify substrates through phosphorylation. In this thesis, I provide several lines of evidence that Cdk5 plays a critical role in synaptic function and plasticity. First, we characterized the function of Cdk5 in learning and memory by region-specific Cdk5 ablation. From multiple Cdk5 conditional knockout mouse models, we determined that Cdk5 is essential for memory formation and synaptic plasticity. Loss of Cdk5 in the hippocampus disrupts the cAMP pathway due to increased phosphodiesterase proteins. This dysregulation of cAMP signaling can be attenuated by a phosphodiesterase inhibitor to restore levels of protein phosphorylation, synaptic plasticity, and memory. Moreover, forebrain-specific deletion of Cdk5 affected multiple aspects of behavior that can partially be rescued by lithium treatment. We next identified the N-type calcium channels as a presynaptic substrate of Cdk5. We described how Cdk5-mediated phosphorylation of the N-type calcium channel increased calcium influx and channel open probability. This in turn enhanced the association of the N-type calcium channel with the active zone protein RIM1, which impacted vesicle docking and neurotransmission. Finally, we identified the postsynaptic density protein Shank3 as a Cdk5 substrate and observed that Cdk5-mediated phosphorylation of Shank3 plays a critical role in maintaining dendritic spine morphology and synaptic plasticity. Our collective results demonstrate a central role for Cdk5 in regulating both presynaptic and postsynaptic functions and provide better insight into how specific targets of Cdk5 can impact a general mechanism underlying synaptic transmission, synaptic plasticity, and cognitive function.
by Susan C. Su.
Ph.D.in Neuroscience