Neurotrophins and consolidation of learning-related synaptic plasticity

BDNF和其他神经营养因子(NTS)在哺乳动物神经系统中具有广泛而强大的作用， 并被认为与突触的可塑性、学习和记忆以及一些精神疾病有关 以及神经疾病，包括阿尔茨海默病、帕金森氏病、亨廷顿病、雷特 综合症、毒瘾、精神分裂症和抑郁症。然而，NTS如何在细胞和 突触的水平还不是很清楚。例如，目前还不清楚NTS是否被释放或作用于 突触前或突触后神经元，或多个哺乳动物NT是否以及如何在单个突触相互作用。海兔属 感觉运动神经元细胞培养是解决这类问题的理想系统。我们之前已经 鉴定了Aplysia BDNF同源基因(APNT)及其Trk受体(ApTrk)，并发现它们对 长期促进(LTF)的诱导和短期(ST)向早期中期(IT)的巩固 促进。我们的结果并不支持我们和其他人所期望的简单的线性级联，而是支持 揭示APNT在两个突触反馈环中扮演着令人惊讶的角色：[1]作为突触前的自分泌信号 放大所需分子的正反馈环路，[2]既是顺行又是逆行 跨突触反馈环中的信号，协调突触前和突触后的机制 车厢。这些环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。我们现在建议将这些研究扩展到三个新方向： 1.APNT和ApTrk在长期可塑性巩固中的作用我们将调查APNT的角色 和ApTrk在早期IT向晚期IT和LT可塑性的巩固中。我们亦会探讨 反馈环，并研究APNT和ApTrk在基因调控和Pre和Pre-2组装中的作用 突触生长过程中的突触后成分。 2.APNT的前体和成熟亚型的作用。与其他神经营养因子一样，APNT有亲和型和成熟型 其相关功能尚不清楚。研究NT的这些亚型的作用在 海兔系统，只有一种神经营养因子。我们的初步结果表明，假设 从感觉神经元释放成熟形式可能起到自分泌信号的作用，有助于诱导 易化，而运动神经元释放Pro形式可能起到逆行信号的作用， 可能通过与CPEB或PKM相互作用来稳定。我们将通过几种方式检验这一假设。 3.APNT和ApTrk在行为学习中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学习的机制 海兔虹吸性戒断反射的制备。我们现在将利用这一准备来探索 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.