Abstract Body

Major depressive disorder (MDD) affects over 300 million people worldwide. Currently 30-50% of patients are treatment resistant necessitating novel therapeutic targets. Previously, our lab showed that the antidepressant Venlafaxine rescues working memory in a stress mouse model combined with increased gamma power and sharp wave ripple (SWR) abundance, which are the neural correlates of learning and memory. The increase in gamma power and SWRs were dependent on Matrix Metalloproteinase-9 (MMP-9), altered in many psychiatric disorders including MDD, suggesting MMP-9 modulation as a novel mechanism for treating MDD. To investigate how modulation of MMP-9 impairs learning and memory, my research uses varied cellular and molecular techniques to answer the question: How does MMP-9 inhibition impair learning and memory in the zebrafish model? Behaviorally, we have corroborated our hypothesis that MMP-9 inhibition impairs working memory. At the cellular level MMP-9 inhibition changes the excitation to inhibition (E/I) balance in the brain as evidenced by a decrease in SWR abundance. Molecularly, the change in E/I can be partially explained by a decrease in GluA4 and Kv3.1 receptors, both of which are predominantly expressed by Parvalbumin positive (PV) neurons – a neuronal population critical for both gamma oscillations and SWR events. Though future studies will examine MMP-9 associated changes in pyramidal neurons, molecular changes in PV neurons could contribute to impaired gamma oscillations and working memory in this model organism. The implications of this research lie in the potential of MMP-9 to directly modulate E/I balance and learning and memory in zebrafish.