MMP-9 activity modulates sharp wave ripple events in the zebrafish hippocampus leading to cognitive deficits

项目总结/摘要 全世界有超过3亿人和17%的美国人口患有重大疾病。 抑郁症（MDD），一种异质性和复发性疾病，无法治愈。MDD被认为是 世界范围内残疾的主要原因，症状是依赖于记忆的记忆障碍。这些 记忆依赖于多巴胺能主细胞（PC）和GABA能之间的精细调节的相互作用。 小清蛋白阳性（PV+）中间神经元，其引起尖波涟漪（SWR）事件。SWR事件是 快速振荡（129-220 Hz）与清醒记忆轨迹的压缩重放有关 的 对这些神经元的结构和/或放电的调制敏感。 患有MDD的患者表现出与海马神经元相关的海马体积减小。 记忆障碍动物模型表明海马体积的减少是由于海马神经元的数量减少， PC分支和树突棘形成。PC简化和PV+中间神经元的增加将 使精细调谐的海马网络不稳定，损害SWR事件，导致海马记忆 损伤 抗抑郁治疗，虽然在不到70%的确诊患者中有效， 树枝化和树突棘形成，并可能减少PV+中间神经元放电，导致 增加SWR事件和更好的认知表现。 我的实验室以前的工作表明，抗抑郁药治疗后SWR的增加 是基质金属蛋白酶-9（MMP-9）依赖性的，明胶酶参与重塑的， 细胞外基质然而，MMP-9活性和通过改变SWRs的调节之间的直接联系， 在PC和PV+神经元中还有待制造。要求两年支持的F31提案包括两个 主要目标。目的1将检验MMP-9抑制导致与MMP-9抑制相关的SWR事件减少的假设。 海马体记忆巩固受损目的2将研究MMP-9抑制如何导致 通过关注1）PC中的特定生化和结构变化， 调节它们的兴奋性（例如，树枝状化，树突形成）和2）PV+兴奋性的变化 斑马鱼初步数据显示，降低MMP-9活性会减少海马中的SWR事件 使用离体全脑局部场电位（LFP）记录的斑马鱼。 这项多学科的研究将通过揭示一些神经科学领域的问题来推动神经科学领域的发展。 参与MDD发病和进展的机制，假设斑马鱼作为筛选新的 抗抑郁药/MMP-9调节剂。这也将提高我们的知识，在电路涉及驻波比 发展

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.