Targeted Neuroepigenetic Editing of CDK5 Regulates Behavior

Chronic stress and memory deficits mount an enormous toll on the global population. While epigenetic modifications driving gene expression related to stress and memory are widely documented, identification of the precise molecular mechanisms by which they regulate specific gene expression remains elusive. Cyclin dependent kinase 5 (Cdk5) is known to regulate both these behaviors and magnitude of these behaviors. Although there is much evidence on the function of Cdk5 protein, very little is known about the regulation of Cdk5 gene expression following stress and learning. We hypothesize that histone modification(s) of Cdk5 is sufficient to regulate its expression, and influence behavioral responses to chronic stress in both male and female animals. We thus sought to determine the spatiotemporal regulation of Cdk5 expression by both chronic unpredictable stress (CUS) and fear conditioning (FC) in mice. We have found that indeed Cdk5 levels vary by phase of FC. Specifically, we measure a significant increase in Cdk5 mRNA levels after memory retrieval, and a decrease after acquisition and consolidation phases. We then utilized targeted epigenetic editing to examine the behavioral and biochemical consequences of Cdk5 histone modifications in CUS & FC. This work will provide a model of stress and memory-evoked chromatin remodeling at Cdk5, and the causal relevance of Cdk5 transcriptional regulation to stress- and memory- induced behavior. Finally, the identification of such precise mechanisms in stress-mediated gene expression allows for the development of targeted therapeutic treatments.