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

项目摘要/摘要 阿尔茨海默病(AD)是一种高度流行的神经退行性疾病，其特征是学习和 记忆障碍和淀粉样β蛋白(Aβ)的病理性堆积。占案件的60%-70% 在痴呆症方面，这种疾病的患病率和公共卫生成本预计将在全球范围内迅速上升 预期寿命会增加。然而，这种疾病中记忆障碍的原因却知之甚少。 尤其是在淀粉样蛋白积累的早期时间点。在阿尔茨海默病小鼠模型中，早于神经元的年龄 或突触丢失时，观察到海马区尖锐波纹(SWRs)、神经元 在记忆巩固中起关键作用的群体事件。这种颠覆背后的机制是 然而，相对未被探索的是，这项研究中提出的一个关键差距将被检验。当它 淀粉样蛋白堆积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。淀粉样蛋白的积聚 显示干扰小白蛋白(PV)表达抑制性篮子细胞(PVBC)的活性，这些细胞具有 在监管SWR事件中发挥关键作用。PV细胞是独一无二的，因为它们是被包裹的主要神经元亚型 在神经元周围网络(PNNS)中，调节和支持细胞活动的蛋白质细胞外基质的一部分。 这项提议将探索优先淀粉样蛋白诱导的PVBC和周围PNN的破坏是否 它们可以解释SWR事件的变化。平行的生化和电生理研究将寻求 为了确定减少对这类细胞的兴奋性输入是否会导致对海马体的抑制性驱动减少 可能导致在早期淀粉样变性病理中经常观察到的过度兴奋活动。这 通过膜片钳技术监测兴奋性PC的活性，进一步探讨其作用机制 电生理学和钙成像以记录系综动力学。生物物理计算模型将 确定所提出的PVBC-PC机制是否足以解释观察到的SWR和系综扰动。 全细胞生物细胞素注射先进技术培训及计算建模 将有助于在早期确定海马网络破坏的神经机制 淀粉样变性。由于这一活动对巩固记忆至关重要，这些发现将提供一种治疗 目标是潜在地改善记忆力下降。

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.