Trans-synaptic interactions during synaptic plasticity in the hippocampus

描述（由申请人提供）：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突触可塑性的分子机制。最近的研究结果表明，长期增强（LTP）是突触可塑性的一种主要形式，它不是一个单一的过程，即使在单个突触上也是如此。LTP在海马CA3和CA1锥体神经元之间的兴奋性突触中通过独立的突触前和突触后机制表达。考虑到这些突触可塑性的诱导涉及钙离子流入突触后CA1神经元，LTP突触前成分的表达表明存在逆行信号，将信号从突触后CA1神经元转移到突触前CA3细胞。LTP期间的逆行信号传导涉及多种分子机制；然而，没有一个能单独满足所有的需求。在本研究中，我们将研究一氧化氮、整合素和神经元粘附分子L1在LTP逆行信号传导机制中的作用。为了实现这些目标，我们将在单个突触的水平上使用突触前功能的荧光指示器直接可视化功能变化。双光子激光扫描显微镜技术和双光子激光扫描解囊技术将结合电生理工具对表达锥体神经元中各种荧光标记的转基因小鼠急性海马切片进行研究。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH 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.