Determining mechanisms underlying hippocampal network disruption in early amyloid pathology: the role of PV basket cells on sharp wave ripples

确定早期淀粉样蛋白病理中海马网络破坏的机制：PV篮细胞对尖波波纹的作用

• 批准号: 9757488
• 负责人: Adam Caccavano
• 金额: $ 3.23万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9757488
• 关键词: Accounting; Acute; Address; Age; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid; Amyloid beta-Protein; Animal Model; Antiepileptic Agents; Biochemical; Biophysics; Calcium; Cells; Clinical; Clinical Trials; Comorbidity; Computer Simulation; Dementia; Disease; Electrophysiology (science); Equilibrium; Event; Extracellular Matrix Proteins; Fellowship; Frequencies; Functional disorder; Hippocampus (Brain); Image; Impairment; Injections; Learning; Life Expectancy; Mediating; Memory; Memory Loss; Memory impairment; Monitor; Mus; Myoepithelial cell; Neurodegenerative Disorders; Neurons; Parvalbumins; Pathologic; Play; Population; Prevalence; Proteins; Public Health; Pyramidal Cells; Research; Risk; Role; Seizures; Senile Plaques; Slice; Synapses; Techniques; Testing; Therapeutic Intervention; Time; Training; Transgenic Organisms; abeta accumulation; amyloid pathology; biocytin; biophysical model; cell type; cost; experimental study; familial Alzheimer disease; improved; memory consolidation; mild cognitive impairment; mouse model; network dysfunction; patch clamp; synaptic function; targeted treatment; therapeutic target

PROJECT SUMMARY/ABSTRACT Alzheimer’s disease (AD) is a highly prevalent neurodegenerative disease, characterized by learning and memory deficits and the pathological accumulation of amyloid beta (Aβ) protein. Accounting for 60-70% of cases of dementia, the disease has a rapidly expected increase in prevalence and cost to public health as world-wide life expectancy increases. The cause of memory dysfunction in the disease is poorly understood however, particularly at an early time-point of amyloid accumulation. In mouse models of AD, at ages preceding neuronal or synaptic loss, there have been observed alterations in hippocampal sharp wave ripples (SWRs), neuronal population events with a critical role in memory consolidation. The mechanisms underlying this disruption are relatively unexplored however, a critical gap that the research proposed in this fellowship will examine. While it is well-appreciated that amyloid accumulation impairs the synaptic function of excitatory pyramidal cells (PCs), there is growing evidence that inhibitory GABAergic cells are also compromised. Amyloid accumulation has been shown to disrupt the activity of parvalbumin (PV) expressing inhibitory basket cells (PVBCs), cells which have a critical role in regulating SWR events. PV cells are unique in that they are the major neuronal subtype ensheathed in peri-neuronal nets (PNNs), part of the extracellular matrix of proteins that regulate and support cellular activity. This proposal will explore if a preferential amyloid-induced disruption to PVBCs and the PNNs that surround them can account for alterations to SWR events. Parallel biochemical and electrophysiological studies will seek to determine if reduced excitatory input to this cell type results in decreased inhibitory drive to the hippocampal network, potentially causing the hyperexcitable activity often observed in early amyloid pathology. This mechanism will be further explored by monitoring the activity of excitatory PCs, both through patch clamp electrophysiology and calcium imaging to record ensemble dynamics. A biophysical computational model will determine if the proposed PVBC-PC mechanism is sufficient to explain observed SWR and ensemble disruption. The training proposed in the advanced techniques of whole-cell biocytin-injection and computational modeling will facilitate the determination of the neuronal mechanisms underlying hippocampal network disruption in early amyloid pathology. As this activity is critical for memory consolidation, these findings will provide a therapeutic target to potentially ameliorate memory decline.

项目总结/摘要 阿尔茨海默病（AD）是一种高度流行的神经退行性疾病，其特征在于学习和记忆障碍。 记忆缺陷和淀粉样β（Aβ）蛋白的病理性积累。占病例的60-70% 作为痴呆症的一种，这种疾病的流行率和公共卫生费用预计将迅速增加， 预期寿命增加。然而，对这种疾病中记忆功能障碍的原因知之甚少， 特别是在淀粉样蛋白积累的早期时间点。在AD的小鼠模型中，在神经元发育之前的年龄， 或突触丢失，已经观察到海马尖波波纹（SWR），神经元 在记忆巩固中起关键作用的群体事件。这种破坏的机制是 然而，相对未被探索的是，本研究金提议的研究将研究一个关键的差距。虽然 众所周知，淀粉样蛋白积累损害兴奋性锥体细胞（PC）的突触功能， 越来越多的证据表明抑制性GABA能细胞也受到损害。淀粉样蛋白的积累 显示破坏表达小清蛋白（PV）的抑制性篮状细胞（PVBC）的活性， 在调节SWR事件中的关键作用。PV细胞是唯一的，因为它们是主要的神经元亚型， 在周围神经元网（PNN）中，调节和支持细胞活性的蛋白质的细胞外基质的一部分。 该提案将探索是否优先淀粉样蛋白诱导的PVBC和周围PNN的破坏 它们可以解释SWR事件的改变。平行的生物化学和电生理学研究将寻求 以确定对该细胞类型的兴奋性输入的减少是否导致对海马的抑制性驱动的减少 网络，潜在地引起在早期淀粉样蛋白病理学中经常观察到的过度兴奋活性。这 通过膜片钳监测兴奋性PC的活性，将进一步探讨其机制， 电生理学和钙成像来记录整体动力学。生物物理计算模型将 确定提出的PVBC-PC机制是否足以解释观察到的SWR和系综破坏。 在全细胞生物胞素注射和计算建模的先进技术中提出的训练 将有助于确定早期海马网络破坏的神经机制， 淀粉样蛋白病理学由于这种活动对记忆巩固至关重要，这些发现将提供一种治疗方法， 旨在潜在地改善记忆衰退。