Synaptic integration and propagation in CA1 dendrites

描述（申请人提供）：海马体在记忆形成中起重要作用。最被广泛接受的记忆形成理论认为，信息是通过突触强度的活动依赖性变化来存储的，突触强度的变化反过来影响海马体中的网络、功能和信息存储。尽管这个概念被广泛接受，但海马体回路的详细工作原理仍然知之甚少。例如，CA1锥体神经元接受数以万计的突触输入，但尚不清楚树突树不同部位的突触如何不同地影响动作电位的启动。在这里，我们提出了旨在提高我们对CA1锥体神经元树突突触整合的理解的实验。提出的实验将验证一个假设，即来自内嗅皮层（穿孔路径）的突触输入如何整合到CA1神经元的远端根尖树突中。具体来说，我们提出这些突触输入只有当它们足够强大时才能触发轴突动作电位，从而引发由电压依赖性钠和钙通道介导的树突尖峰。我们进一步假设，只有当更多的近端突触被激活或可塑性导致树突兴奋性增强时，表现性路径诱导的树突尖峰才会传播到体细胞。我们提出代谢性谷氨酸受体（mGluR）依赖的突触可塑性与mGluR依赖的树突兴奋性的非突触可塑性协同作用，以增强穿孔通路激活导致轴突动作电位放电的能力。这些实验将有助于我们更好地理解CA1锥体神经元是如何在利用可塑性来存储记忆的电路中发挥作用的。对海马体整合特性的进一步了解对于理解这种大脑结构在记忆中的作用以及癫痫和阿尔茨海默病等疾病如何干扰正常的整合功能和记忆至关重要。

DESCRIPTION (provided by applicant): The hippocampus plays an important role in memory formation. The most widely accepted theory of memory formation posits that information is stored through activity-dependent changes in synaptic strength, which in turn influence network, function and information storage in the hippocampus. Despite this well accepted notion, the detailed workings of hippocampal circuitry remain poorly understood. For instance, CA1 pyramidal neurons receive tens of thousands of synaptic inputs, but it is not known how synapses on different parts of the dendritic tree differentially influence action potential initiation. Here we propose experiments designed to improve our understanding of synaptic integration in the dendrites of CA1 pyramidal neurons. The proposed experiments will test an hypothesis concerning how synaptic inputs from the entorhinal cortex (perforant path) are integrated in the distal apical dendrites of CA1 neurons. Specifically, we propose that these synaptic inputs can only trigger axonal action potentials when they are strong enough to elicit dendritic spikes mediated by voltage-dependent sodium and calcium channels. We posit further that peforant path-induced dendritic spikes propagate to the soma only when more proximal synapses are activated or when plasticity leads to enhanced dendritic excitability. We propose that metabotropic glutamate receptor (mGluR)-dependent synaptic plasticity operates in concert with mGluR-dependent non-synaptic plasticity of dendritic excitability to enhance the ability of perforant path activation to lead to axonal action potential firing. These experiments will lead to a better understanding of how CA1 pyramidal neurons function within the context of a circuit employing plasticity to store memories. Such an improved understanding of the integrative properties of hippocampus is central to understanding the role of this brain structure in memory and how diseases such as epilepsy and Alzheimer's interfere with normal integrative function and memory.