Neurotrophins and consolidation of learning-related synaptic plasticity

BDNF和其他神经营养因子（NT）在哺乳动物神经系统中具有广泛和强大的作用， 被认为与突触可塑性、学习和记忆有关，也与许多精神疾病有关。 和神经系统疾病，包括阿尔茨海默病、帕金森病、亨廷顿病、Rett 综合症、药物成瘾、精神分裂症和抑郁症。然而，神经营养素在细胞和 突触水平还不是很清楚。例如，目前尚不清楚NTs是否从细胞中释放或作用于细胞， 突触前或突触后神经元，或者多个哺乳动物NT是否以及如何在单个突触处相互作用。海兔 感觉运动神经元细胞培养是解决这些类型问题的理想系统。我们之前 鉴定了一种失智症BDNF直系同源物（ApNT）及其Trk受体（ApTrk），并发现它们对 诱导长期促进（LTF）并巩固短期（ST）至早期中期（IT） 便利化我们的结果不支持我们和其他人所期望的简单线性级联，而是 揭示了ApNT在两个突触反馈回路中发挥着令人惊讶的作用：[1]作为突触前神经元的自分泌信号， 正反馈回路，放大所需的分子，[2]作为顺行和逆行 突触前和突触后协调机制的跨突触反馈回路中的信号 隔间这些回路为巩固与学习相关的可塑性提供了新的机制， 我们会做出更广泛的贡献。我们现在建议在三个新的方向上扩展这些研究： 1. ApNT和ApTrk在长期可塑性巩固中的作用我们将研究ApNT的作用 和ApTrk在早期IT到晚期IT的巩固和LT可塑性中的作用。我们亦会探讨 反馈环，并研究ApNT和ApTrk在基因调控和组装前和后的作用。 突触生长级联中的突触后成分。 2. ApNT的原亚型和成熟亚型的作用。像其他神经营养因子一样，ApNT有亲和成熟形式 其相关功能尚不清楚。研究NT的这些同种型的作用在本领域中要容易得多。 神经营养素缺乏症系统，其中只有一个单一的神经营养素。我们的初步结果表明， 从感觉神经元释放成熟形式可能作为一种自分泌信号，有助于诱导 促进，而从运动神经元释放前形式可能作为一个逆行信号，有助于 稳定，也许通过与CPEB或PKM互动。我们将从几个方面来检验这个假设。 3.行为学习过程中ApNT和ApTrk的因果作用及其与其他机制的整合。 神经营养因子在行为学习和记忆中的确切作用也不清楚。为了回答这个问题， 我们一直在研究生理条件下简单形式的学习机制， 准备的Aesthesia虹吸撤退反射。我们现在将利用这一准备来探讨 ApNT和ApTrk及其在行为学习过程中与其他细胞和分子机制的整合。

BDNF and other neurotrophins (NTs) have widespread and powerful roles in the mammalian nervous system, and are thought to be involved in synaptic plasticity, learning, and memory, as well as in a number of psychiatric and neurological disorders including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Rett syndrome, drug addiction, schizophrenia, and depression. However, how NTs function at the cellular and synaptic levels is not well understood. For example, it is not clear whether NTs are released from or act on the pre- or postsynaptic neuron, or whether and how multiple mammalian NTs interact at a single synapse. Aplysia sensory-motor neuron cell culture is an ideal system for addressing these types of questions. We had previously identified an Aplysia BDNF ortholog (ApNT) and its Trk receptor (ApTrk) and found that they are important for the induction of long-term facilitation (LTF) and consolidation of short-term (ST) to early intermediate-term (IT) facilitation. Our results do not support the simple linear cascade that we and others had expected, but rather reveal that ApNT plays surprising roles in two synaptic feedback loops: [1] as an autocrine signal in a presynaptic positive feedback loop that amplifies the molecules required, and [2] as both an anterograde and retrograde signal in a transynaptic feedback loop that coordinates mechanisms in the presynaptic and postsynaptic compartments. These loops provide novel mechanisms for consolidation of learning-related plasticity that could well contribute more generally. We now propose to extend those studies in three new directions: 1. The roles of ApNT and ApTrk in consolidation of long-term plasticity. We will investigate the roles of ApNT and ApTrk in consolidation of early IT to late IT and LT plasticity. We will also explore possible functions of the feedback loops, and investigate the roles of ApNT and ApTrk in gene regulation and the assembly of pre- and postsynaptic components in a synaptic growth cascade. 2. The roles of pro and mature isoforms of ApNT. Like other neurotrophins ApNT has pro and mature forms whose relative functions are unclear. Investigating the roles of those isoforms of a NT is much easier in the Aplysia system, which only has a single neurotrophin. Our preliminary results suggest the hypothesis that release of the mature form from sensory neurons may act as an autocrine signal that contributes to induction of facilitation, whereas release of the pro form from motor neurons may act as a retrograde signal that contributes to stabilization, perhaps by interacting with CPEB or PKM. We will test that hypothesis in several ways. 3. The causal roles of ApNT and ApTrk and their integration with other mechanisms during behavioral learning. The exact roles of neurotrophins in behavioral learning and memory are also unclear. To address that question, we have been studying mechanisms of simple forms of learning under physiological conditions in a reduced preparation of the Aplysia siphon withdrawal reflex. We will now use that preparation to explore the causal roles of ApNT and ApTrk and their integration with other cellular and molecular mechanisms during behavioral learning.