Project Summary/AbstractThe most effective treatment identified to date for severe mood and psychotic disorders is electroconvulsivetherapy (ECT). These mental illnesses affect >6.5% of adults in the U.S. and account for a major proportion ofdisability in society. Despite its efficacy the negative image of ECT drastically limits its use. Determining themechanism by which ECT resolves severe psychiatric symptoms may facilitate the design of alternativetherapies to engage these mechanisms without seizure and its perceived negative consequences. Towardsthis goal this research team proposes to investigate overarching hypothesis that early growth responsegene 3 (Egr3) which is activated by ECS and orchestrates synaptic plasticity memory and regulationof growth factors is a key mediator of therapeutic efficacy of ECS. The research team will test this theoryby evaluating two complementary hypotheses. First that Egr3 is required for ECT to regulate depression-related physiologic processes and to reverse depressive behavior. Second that Egr3 upregulation issufficient to reverse these brain and behavioral changes in the absence of seizure. This will beaccomplished using innovative adeno-associated viral (AAV) constructs that express short hairpin RNAs toknock down Egr3 and scrambled RNA controls. Infusing these constructs into the ventral hippocampus (VH) aregion critical for mood regulation will allow determination of how Egr3 coordinates the response to ECS.In Specific Aim 1 this research team proposes to determine the roles of Egr3 in ECS-induced growthfactor expression neurogenesis and dendritic sprouting in the hippocampus. In addition to AAVconstructs they will administer EdU (5-ethynyl-2'-deoxyuridine) to mark newly born neurons in the VHfollowed by ECS vs. sham procedures. They will use immunohistochemistry to quantify VH neurogenesis andBDNF activation. Biocytin filling of AAV-positive neurons and adjacent controls will be used to determine therole of Egr3 in mediating the effect of ECS on the hippocampal neuron morphology and connectivity.In Specific Aim 2 this research team proposes to ascertain the necessity of Egr3 for the antidepressanteffect of ECS on depression-like behavior in male and female mice. The team will use chronic mild stressto induce a depression-like state in mice and test the requirement for Egr3 in the VH for the reversal of thisstate by ECS. Anti-depressant like response will be assessed using the validated forced swim test (FST).Knockdown of Egr3 is expected to abrogate the antidepressant-like effect of ECS on FST immobility.Moreover to establish sufficiency of Egr3 to reduce depression-like behavior (i.e. even in the absence ofseizure) they will infuse an Egr3 construct into the VH which is expected to reduce immobility in the FST.The impact of this study will be the successful identification of the molecular mechanism for the efficacy ofECT. This will provide both fundamental insight into the neural dysfunction shared among mood and psychoticillnesses as well as potentially reveal novel targets for next-generation therapies that do not require seizure.