SYNAPTIC PLASTICITY IN HIPPOCAMPAL MOSSY CELLS

齿状苔藓细胞是一种相对罕见的神经元群体， 极易受过度兴奋所致的兴奋毒性损害 输入。而导致这一现象的细胞机制 漏洞是未知的，一个潜在的解释在于 苔藓细胞调节自身力量的特殊能力 突触输入。我观察到，在经历了短暂的 细胞内注射的去极化电流脉冲，有一个 自发性兴奋性显著而持久的增强 在同一细胞中记录突触后电位(EPSP)。我 假设这种现象，去极化相关的增强， 可能通过产生 积极反馈途径：相对较短的时期 去极化时，如经历了几次自发的EPSP 重叠，可能会启动这一机制--增强后续的EPSP和 造成失控的去极化和细胞死亡的可能性。 这种类型的渐进式去极化，由大幅度启动 在颞叶癫痫的体外模型中观察到EPSPS 其中苔藓细胞选择性地易受攻击。在中国的实验 本提案中概述的大鼠海马区切片旨在 揭示这种形式的可塑性背后的机制。我们专注于 颗粒细胞/苔藓细胞可塑性机制的初步探讨 突触，因为我的初步数据表明DRP的大部分可能是 可以用这个突触的调制来解释。通过检查的属性 微型EPSCs在DRP诱导前后，我们希望能确定 突触前或突触后部位是否受DRP调节，从而 DRP是否代表一种跨突触可塑性。 初步实验表明，DRP与 在海马区研究的短时程增强(STP)；我们预计 这里提出的实验将导致对 突触增强的一般原理。潜在的角色 DRP Will诱导苔藓细胞内钙的积累 使用钙络合剂和钙敏感荧光进行测试 染料，福拉-2。然后，我们将检查对增强的贡献 通过刺激其他齿状突起和海马神经元 使用双重记录和切片将突触连接到苔藓细胞 其中海马区和/或齿状回的亚区 已删除。我预计这些研究将确定一种形式的 “自我增强”是肝门兴奋性毒性损伤的原因 神经细胞的体外培养，并可能对糖尿病的病因有新的认识 起病于海马区的颞叶癫痫。

Dentate mossy cells are a relatively rare population of neurons that are extremely vulnerable to excitotoxic damage from excess excitatory input. While the cellular mechanisms responsible for this vulnerability are not known, one potential explanation lies in the unusual ability of mossy cells to modulate the strength of their own synaptic inputs. I observed that following short periods of intracellularly-injected depolarizing current pulses, there was a dramatic and prolonged enhancement of spontaneous excitatory postsynaptic potentials (EPSPs) recorded in that same cell. I hypothesized that this phenomenon, depolarization-related potentiation, may contribute to the vulnerability of the mossy cells by generating a positive feedback pathway: relatively brief periods of depolarization, such as experienced when several spontaneous EPSPs overlap, may engage this mechanism--potentiating subsequent EPSPs and creating the potential for a runaway depolarization and cell death. This type of progressive depolarization, initiated by large amplitude EPSPs, has been observed in an in vitro model of temporal lobe epilepsy in which mossy cells are selectively vulnerable. The experiments in rat hippocampal slices outlined in this proposal are designed to uncover the mechanisms that underlie this form of plasticity. We focus first on the mechanisms of plasticity at the granule cell/mossy cell synapse since my preliminary data suggests that much of DRP could be explained by modulation of this synapse. By examining properties of miniature EPSCs before and after induction of DRP, we hope to ascertain whether the pre- or postsynaptic site is modulated by DRP, and thus whether DRP represents a form of trans-synaptic plasticity. Preliminary experiments suggest that DRP shares many similarities with short-term potentiation (STP) studied in the hippocampus; we anticipate that the experiments proposed here will lead to new understanding of general principles of synaptic potentiation. The potential role calcium accumulation in the mossy cells in the induction of DRP will be tested using calcium chelators and the calcium-sensitive fluorescent dye, fura-2. We then will examine the contribution to the potentiation from spiking in other dentate and hippocampal neurons which are synaptically coupled to mossy cells using dual recordings and slices in which subfields of the hippocampus and/or dentate gyrus have been removed. I anticipate that these studies will determine if a form of "self-potentiation" is responsible for the excitotoxic damage to hilar neurons in vitro and may lead to new insights into the etiology of hippocampal-onset temporal lobe epilepsy.