Diversity of Nicotinic Synapses in Sympathetic Ganglia

这个项目的长期目标是确定神经元烟碱受体的细胞表达的多样性如何有助于哺乳动物交感神经节的突触功能。这项研究将在乌克兰基辅进行，作为NIH资助#R01 NS 21065的扩展。该项目的中心假设指出，神经元服务不同的效应器模式表达不同的组合烟碱受体亚基，作为一种手段，用于调节快速兴奋性突触后电位的持续时间，从而控制节前活动的突触放大。拟议的实验将使用电生理学来评估大鼠交感神经元和副交感神经元中的烟碱受体。具体目标1是确定区分交感神经元和副交感神经元的功能子集上的烟碱受体的动力学特征。这些数据的综合后果，然后将使用计算模型，模拟自主神经节的突触活动进行评估。具体目标2是通过系统表征新型开放通道阻滞剂和烟碱受体α亚基抗血清，扩展血管交感神经元突触受体的药理学特征。我们的目标是开发一个合理的基础，设计新的化合物，将是高度选择性的血管交感神经元和其他自主模式。这些化合物可用于进一步剖析不同自主细胞群的作用，并可能具有临床应用。具体目标3是确定α-银环蛇毒素敏感的烟碱受体是否有助于交感神经节中的快速突触传递。这将测试是否最近的工作在鸟类自主神经节也适用于哺乳动物神经元，已知表达α-7烟碱亚基。解决每个具体目标所提出的问题将对我们理解神经节整合产生根本影响。自主神经节中的烟碱突触对公共卫生很重要，因为它们对于被衰老和神经疾病破坏的自主行为（例如，对运动的心血管适应、生殖、体温调节和对压力的防御性适应）是必不可少的。

The long-term goal of this project is to determine how diversity in the cellular expression of neuronal nicotinic receptors contributes to synaptic function in mammalian sympathetic ganglia. This research will be done in Kiev, Ukraine as an extension of NIH grant #R01 NS21065. The project's central hypothesis states that neurons serving different effector modalities express distinct combinations of nicotinic receptor subunits, as a means for regulating the duration of fast excitatory postsynaptic potentials and thereby controlling the synaptic amplification of preganglionic activity. The proposed experiments will use electrophysiology to assess nicotinic receptors in rat sympathetic and parasympathetic neurons. Specific aim 1 is to identify kinetic features that distinguish nicotinic receptors on functional subsets of sympathetic and parasympathetic neurons. The integrative consequences of these data will then be evaluated using computational models that simulate synaptic activity in autonomic ganglia. Specific aim 2 is to extend the pharmacological profile of synaptic receptors on vasomotor sympathetic neurons by systematic characterization of novel open-channel blockers and antisera against alpha-subunits of nicotinic receptors. The goal is to develop a rational basis for designing new compounds that would be highly selective for vasomotor sympathetic neurons and other autonomic modalities. Such compounds could be used to further dissect the roles of different autonomic cell groups and may have clinical applications. Specific aim 3 is to determine whether alpha-bungarotoxin-sensitive nicotinic receptors contribute to fast synaptic transmission in sympathetic ganglia. This will test whether recent work on avian autonomic ganglia also holds true in mammalian neurons that are known to express the alpha-7 nicotinic subunit. Resolving the issues posed by each specific aim would have fundamental implications for our understanding of ganglionic integration. Nicotinic synapses in autonomic ganglia are important for public health because they are essential for autonomic behaviors that are disrupted by aging and neurological disease (e.g. cardiovascular adaptation to exercise, reproduction, thermoregulation and defensive adaptation to stress).