PROJECT SUMMARY/ABSTRACT Over 300 million people worldwide and 17% of the United States population suffer from Major Depressive Disorder (MDD), a heterogenous and recurrent disorder with no cure. MDD is considered the leading cause of disability worldwide with hippocampal-dependent memory impairments as a symptom. These memories rely on the finely tuned interplay between glutamatergic principal cells (PC) and GABAergic parvalbumin positive (PV+) interneurons that give rise to sharp wave ripple (SWR) events. SWR events are fast oscillations (129-220 Hz) associated with the compressed replay of awake memory traces that are sensitive to modulations in the structure and/or firing of these neurons. Patients suffering from MDD exhibit a decreased hippocampal volume associated with hippocampal memory impairments. Animal models suggest that a decreased hippocampal volume is the result of decreased PC arborization and dendritic spine formation. PC simplification and an increase in PV+ interneurons will destabilize the finely tuned hippocampal network, impairing SWR events, resulting in hippocampal memory impairments. Antidepressant treatment, though effective in less than 70% of diagnosed patients, increases PC arborization and dendritic spine formation and potentially decreases PV+ interneuron firing, leading to an increase in SWR events and better cognitive performance. Previous work from my laboratory has shown that the increase in SWRs after antidepressant treatment was matrix metalloproteinase-9 (MMP-9) dependent, a gelatinase involved in the remodeling of the extracellular matrix. However, a direct link between MMP-9 activity and modulation of SWRs through changes in PCs and PV+ neurons is yet to be made. This F31 proposal requesting 2 years of support encompasses two main aims. Aim 1 will test the hypothesis that MMP-9 inhibition leads to a decrease in SWR events associated with impaired hippocampal memory consolidation. Aim 2 will investigate how MMP-9 inhibition leads to a decrease in SWR events by focusing on 1) the specific biochemical and structural changes in PCs that modulate their excitability (e.g., arborization, dendritic formation) and 2) changes in PV+ excitability using zebrafish. Preliminary data shows that decreasing MMP-9 activity decreases SWR events in the hippocampus of zebrafish using ex vivo whole-brain Local Field Potential (LFP) recordings. This multidisciplinary research will advance the field of neuroscience by uncovering some of the mechanisms involved in the onset and progression of MDD postulating zebrafish as a tool to screen for novel antidepressants/MMP-9 modulators. It will also enhance our knowledge in the circuitry involved in SWR development.