Trans-synaptic interactions during synaptic plasticity in the hippocampus

项目摘要：为了理解学习和记忆，我们必须首先阐明 调节中枢神经系统中突触的可塑性。最近的研究结果表明，长时程增强(LTP)是一种主要的形式 突触可塑性不是一个单一的过程，即使在单个突触上也是如此。LTP由独立的 海马CA3区和CA1区锥体神经元兴奋性突触的突触前和突触后机制 海马体。鉴于这些突触可塑性的诱导涉及钙离子的内流 在突触后CA1神经元中，LTP突触前成分的表达表明 一种逆行信号，将信号从突触后CA1神经元传递到突触前CA3细胞。 不同的分子机制参与了LTP过程中的逆行信号传递；然而，并不是单独的 满足所有要求。在这项提案中，我们将研究一氧化氮、整合素和 神经元黏附分子L1在LTP逆行信号传递机制中的作用。为了实现这些目标， 我们将使用突触前功能的荧光指示器在一个水平上直接可视化功能变化 单一突触。双光子激光扫描显微镜和双光子激光扫描消去技术将 与电生理工具联合应用于转基因小鼠的急性海马片 在锥体神经元中表达各种荧光标记。相关性：长时程增强(LTP)是神经元之间信号的使用依赖性增强。 大脑。LTP被认为是调节学习和记忆的关键过程。为了更好地理解 学习和记忆，并进一步发现预防疾病破坏这些基本功能的方法 为了研究LTP在人类中的能力，我们将研究具有适当基因突变的小鼠的LTP分子基础。

Project summary: To understand learning and memory, we must first elucidate the molecular machinery that regulates synaptic plasticity in the CNS. Recent results indicate that long-term potentiation (LTP), a major form of synaptic plasticity, is not a unitary process, even at a single synapse. LTP is expressed by independent presynaptic and postsynaptic mechanisms at excitatory synapses between CA3 and CA1 pyramidal neurons in the hippocampus. Given that the induction of plasticity at these synapses involves the influx of calcium ions into postsynaptic CA1 neurons, the expression of the presynaptic component of LTP suggests the existence of a retrograde signal that transfers a signal from the postsynaptic CA1 neuron to the presynaptic CA3 cell. Various molecular mechanisms have been implicated in retrograde signaling during LTP; however, none alone satisfies all of the requirements. In this proposal, we will examine the roles of nitric oxide, integrins, and neuronal adhesion molecule L1 in mechanisms of retrograde signaling during LTP. To accomplish these goals, we will directly visualize functional changes using fluorescent indicators of presynaptic function at the level of a single synapse. Two-photon laser scanning microscopy and 2-photon laser scanning uncaging techniques will be used in combination with electrophysiological tools in acute hippocampal slices from transgenic mice expressing various fluorescent markers in pyramidal neurons. Relevance: Long-term potentiation (LTP) is the use-dependent enhancement of the signal between neurons in the brain. LTP is thought to be a key process that regulates learning and memory. To better understand learning and memory and further the discovery of ways to prevent disease from disrupting these essential abilities in humans, we will investigate the molecular bases of LTP in mice with appropriate genetic mutations.