Show simple item record

dc.contributor.advisorLi-Huei Tsai.en_US
dc.contributor.authorSu, Susan C. (Susan Chih-Chieh)en_US
dc.contributor.otherMassachusetts Institute of Technology. Department of Brain and Cognitive Sciences.en_US
dc.date.accessioned2013-06-17T19:01:56Z
dc.date.available2013-06-17T19:01:56Z
dc.date.copyright2012en_US
dc.date.issued2013en_US
dc.identifier.urihttp://hdl.handle.net/1721.1/79141
dc.descriptionThesis (Ph. D. in Neuroscience)--Massachusetts Institute of Technology, Dept. of Brain and Cognitive Sciences, February 2013.en_US
dc.descriptionThis electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.en_US
dc.descriptionCataloged from student-submitted PDF version of thesis. "February 2013." Page 192 blank.en_US
dc.descriptionIncludes bibliographical references.en_US
dc.description.abstractThe 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.en_US
dc.description.statementofresponsibilityby Susan C. Su.en_US
dc.format.extent192 p.en_US
dc.language.isoengen_US
dc.publisherMassachusetts Institute of Technologyen_US
dc.rightsM.I.T. theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. See provided URL for inquiries about permission.en_US
dc.rights.urihttp://dspace.mit.edu/handle/1721.1/7582en_US
dc.subjectBrain and Cognitive Sciences.en_US
dc.titleRegulation of synaptic function and plasticity by cyclin-dependent kinase 5en_US
dc.typeThesisen_US
dc.description.degreePh.D.in Neuroscienceen_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Brain and Cognitive Sciences.en_US
dc.identifier.oclc844347890en_US


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record