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

MMP-9 活性调节斑马鱼海马中的尖锐波涟漪事件，导致认知缺陷

• 批准号: 10386410
• 负责人: Ismary Blanco
• 金额: $ 2.64万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2022-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10386410
• 关键词: AMPA Receptors; Acids; Action Potentials; Affect; Animal Model; Antidepressive Agents; Atrophic; Biochemical; Brain; Calcium; Cells; Chronic stress; Cognitive; Cognitive deficits; Data; Data Analyses; Dendritic Spines; Development; Diagnosis; Disease; Electrophysiology (science); Environmental Risk Factor; Event; Exhibits; Extracellular Matrix; Fellowship; Future; Gelatinase A; Gelatinase B; Generations; Glutamates; Goals; Hippocampus (Brain); Impaired cognition; Impairment; Interdisciplinary Study; Interneurons; Knowledge; Laboratories; Learning; Link; Major Depressive Disorder; Matrix Metalloproteinases; Measures; Memory; Memory impairment; Modeling; Molecular; Mus; Neurons; Neurosciences; Parvalbumins; Patients; Persons; Pharmacology; Population; Probability; Public Health; Recurrence; Request for Proposals; Research; Role; SB 3CT compound; Stress; Structure; Symptoms; Synapses; Techniques; Testing; Therapeutic; Therapeutic Intervention; Transgenic Organisms; United States; Work; Zebrafish; awake; cognitive performance; disability; fortification; improved; innovation; memory consolidation; novel; patch clamp; predictive marker; skills; tool; training opportunity; transmission process; venlafaxine

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.

项目概要/摘要 全球有超过 3 亿人（其中 17% 的美国人口）患有严重疾病 抑郁症 (MDD) 是一种异质性、反复发作的疾病，无法治愈。 MDD 被认为是 以海马依赖性记忆障碍为症状的全球残疾的主要原因。这些 记忆依赖于谷氨酸能主细胞 (PC) 和 GABA 能细胞之间精细调节的相互作用 小清蛋白阳性 (PV+) 中间神经元引起尖锐波波纹 (SWR) 事件。 SWR 事件是 与清醒记忆痕迹的压缩重放相关的快速振荡（129-220 Hz） 那是 对这些神经元的结构和/或放电的调节敏感。 患有 MDD 的患者表现出与海马体相关的海马体积减少 记忆障碍。动物模型表明海马体积减少是由于 PC 树枝化和树突棘形成。 PC 的简化和 PV+ 中间神经元的增加将 破坏精细调节的海马网络的稳定性，损害 SWR 事件，导致海马记忆 损伤。 抗抑郁治疗虽然对不到 70% 的确诊患者有效，但会增加 PC 树枝化和树突棘形成，并可能减少 PV+ 中间神经元放电，从而导致 SWR 事件的增加和更好的认知表现。 我实验室之前的工作表明，抗抑郁治疗后 SWR 有所增加 依赖于基质金属蛋白酶 9 (MMP-9)，这是一种参与细胞重塑的明胶酶 细胞外基质。然而，MMP-9 活性和 SWR 通过变化的调节之间存在直接联系 在 PC 和 PV+ 神经元中的应用尚未完成。该 F31 提案请求 2 年支持，包括两个内容 主要目标。目标 1 将检验以下假设：MMP-9 抑制会导致相关 SWR 事件减少 海马记忆巩固受损。目标 2 将研究 MMP-9 抑制如何导致 通过关注 1) PC 中特定的生化和结构变化来减少 SWR 事件 调节它们的兴奋性（例如，树枝化、树突形成）和 2）PV+ 兴奋性的变化 斑马鱼。初步数据表明，降低 MMP-9 活性会减少海马体中的 SWR 事件 使用离体全脑局部场电位（LFP）记录对斑马鱼进行研究。 这项多学科研究将通过揭示一些问题来推动神经科学领域的发展 MDD 发病和进展的机制假设斑马鱼作为筛选新发现的工具 抗抑郁药/MMP-9 调节剂。它还将增强我们对 SWR 所涉及电路的了解 发展。