Date of Award

Fall 9-21-2020

Document Type


Degree Name

Master of Science (MS)



First Advisor

Dr. Ashok N. Hegde

Second Advisor

Dr. Ellen France

Third Advisor

Dr. Kasey A. Karen


Maintenance of long-term synaptic plasticity requires gene expression mediated by cAMP-responsive element binding protein (CREB). Gene expression driven by CREB can commence only if the inhibition by a transcriptional repressor ATF4 (activating transcription factor 4; aka CREB2) is relieved. Previous research showed that the removal of ATF4 occurs through ubiquitin-proteasome-mediated proteolysis. Using chemically induced hippocampal long-term potentiation (cLTP) as a model system, we investigated the mechanisms that control ATF4 degradation. We observed that ATF4 phosphorylated at Serine-219 increases upon induction of cLTP and decreases by about 30 min thereafter. Proteasome inhibitor β-lactone prevents the decrease in ATF4. We found that the phosphorylation of ATF4 is mediated by cAMP-dependent protein kinase. Our initial experiments towards the identification of the ligase that mediates ubiquitination of ATF4 revealed a possible role for β-transducin repeat containing protein (βTrCP). Regulation of ATF4 degradation is likely to be a mechanism for determining the threshold for gene expression underlying maintenance of long-term synaptic plasticity and by extension, long-term memory.