Inhibition of MMP-9 Activity Impairs Working Memory in Zebrafish Through Changes in Overall Hippocampal Excitation

点击翻译按钮获取中文摘要

ABSTRACT Over 300 million people worldwide suffer from Major Depressive Disorder (MDD), a heterogenous disorder with no cure. MDD is associated with hippocampal-dependent memory impairments, including severe working memory (WM) deficits. The encoding and consolidation of newly acquired experiences rely on the finely tuned interplay between pyramidal excitatory neurons and GABAergic parvalbumin positive (PV) interneurons that control the excitation to inhibition (E/I) balance in the hippocampus. The interplay between these two neuronal populations in the hippocampus results in the temporally coordinated firing of pyramidal neurons that give rise to theta/gamma oscillations and sharp wave ripple (SWR) events, underlying the proper encoding and consolidation of information, respectively. In patients suffering from MDD both encoding and consolidation of experiences are impaired due to a shift in their hippocampal E/I balance to a less excitatory state. Strikingly, our lab has shown that the antidepressant venlafaxine rescues WM in a stress mouse model through increasing gamma oscillations and SWR abundance in the hippocampus. This increase was dependent on Matrix Metalloproteinase-9 (MMP-9), a gelatinase that remodels the extracellular matrix and is altered in MDD. Following in this line of research, my dissertation focuses on the role of MMP-9 activity in the proper functioning of hippocampal-dependent neuronal networks in the zebrafish. My behavioral data indicates that MMP-9 inhibition impairs WM, which was accompanied by changes in the E/I balance in the hippocampus to a less excitatory state as evidenced by a decrease in SWR abundance. Additionally, my proteomics data suggest that the shift in E/I balance can be explained by changes in both pyramidal and PV neurons. For instance, plasminogen, a marker for excitatory neuronal activity was significantly decreased after MMP-9 inhibition. Components of the Perineuronal Nets (PNN), that regulate the firing of PV neurons, such as versican, were significantly increased. These changes contribute to a less excitatory hippocampus similar to what we see in patients suffering from MDD. My data then postulates MMP-9 activity modulation as a potential therapeutic target to treating depression-related symptoms. For the D-SPAN F99/K00 training grant, I have two specific aims. For Aim 1 (F99 phase) I have outlined my progress thus far and how I will master whole-cell patch clamp and optical sensing recordings to distinguish how MMP-9 inhibition differentially affects the intrinsic properties of pyramidal and PV neurons and whether theta/gamma oscillations are also affected. After successfully graduating, for the K00 phase I will join my ideal postdoctoral lab at an R1 institution dedicated to scientific excellence, professional and intellectual development, networking, and increasing and retaining diverse scientists in academia. I will also continue studying the cellular and molecular mechanisms leading to neural circuitry impairment during degeneration while fostering my training towards becoming a well-rounded neuroscientist researcher and mentor.