Diversity of Nicotinic Synapses in Sympathetic Ganglia

该项目的长期目标是确定神经元烟碱受体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第#R01 NS21065号拨款的延伸。该项目的中心假设是，服务于不同效应器模式的神经元表达不同的尼古丁受体亚单位组合，作为调节快速兴奋性突触后电位的持续时间，从而控制突触放大节前活动的一种手段。拟议的实验将使用电生理学来评估大鼠交感和副交感神经元中的尼古丁受体。具体目标1是确定区分交感和副交感神经元功能亚群上的烟碱受体的动力学特征。然后将使用模拟自主神经节中突触活动的计算模型来评估这些数据的综合结果。具体目标2是通过系统地表征新型开放通道阻滞剂和抗尼古丁受体α亚基的抗血清，扩大血管运动性交感神经元上突触受体的药理学特征。其目标是为设计对血管运动性交感神经元和其他自主神经模式具有高度选择性的新化合物开发一个合理的基础。这些化合物可以用来进一步剖析不同自主神经细胞群的作用，并可能有临床应用。具体目标3是确定α-银环蛇毒素敏感的烟碱受体是否参与交感神经节的快速突触传递。这将测试最近对鸟类自主神经节的研究是否也适用于已知的表达α-7烟碱亚单位的哺乳动物神经元。解决每个具体目标提出的问题将对我们理解神经节整合具有根本意义。自主神经节中的尼古丁突触对公共健康很重要，因为它们对于被衰老和神经系统疾病破坏的自主行为(如运动的心血管适应、生殖、体温调节和应激的防御适应)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).