MODULATION OF OLFACTORY CIRCUITS

嗅觉回路的调节

• 批准号: 2869225
• 负责人: Paul Q Trombley
• 金额: $ 10万
• 依托单位: FLORIDA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-30 至 2001-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2869225
• 关键词: GABA receptor; NMDA receptors; copper; dipeptides; electrophysiology; excitatory aminoacid; gamma aminobutyrate; glycine receptors; neural transmission; neuroregulation; neurotransmitter receptor; neurotransmitters; olfactory lobe; synapses; tissue /cell culture; voltage /patch clamp; zinc

Primary synaptic circuits throughout most of the CNS, including the olfactory bulb, use amino acid transmitters including glutamate, GABA, and glycine. Despite progress in the characterization of these circuits, little is known about their modulation by endogenous neuroactive substances. Given the accepted roles of amino acid transmitters in synaptic plasticity and some forms of neuropathology it is possible that modulation of amino acid receptors by endogenous substances influences these processes. Thus, it is important to clarify mechanisms underlying such modulation. The transition metals, zinc and copper, represent endogenous neuroactive substances which are highly concentrated in the bulb. Because these transition metals have been shown to be released by neurons in other regions of the CNS, it has been proposed that they function as neuromodulators during synaptic transmission. In addition, the implication of zinc and/or copper in several neuropathologic conditions (Pick's disease, Wilson's disease, epilepsy, and Alzheimer's disease) suggests that these metals may be associated with abnormal modulation of synaptic pathways that use amino acid transmitters. This hypothesis is further supported by pilot data demonstrating modulation of amino acid-mediated currents by zinc and copper. Along with zinc and copper, the dipeptide carnosine also is found in the olfactory system. Although it has been proposed as a transmitter or modulator, attempts at verifying this hypothesis have produced equivocal results. However, the finding that olfactory sensory neurons contain zinc, carnosine, and glutamate, suggests the potential for a combined role in neuromodulation. Our pilot data suggesting that carnosine modulates the actions of zinc and copper on amino acid receptors on olfactory bulb neurons also are consistent with this possibility. The well-characterized circuits and rich supply of neuroactive substances make the mammalian olfactory bulb an ideal preparation for studying neuromodulation. Furthermore, olfactory dysfunction is an early manifestation of several neuropathologic conditions associated with aging (e.g. Parkinson's disease, Alzheimer's disease) that are thought to be linked to amino acid transmitter pathology. The goal of this proposal is to explore the modulatory actions of zinc, copper and carnosine on NMDA, GABAA and glycine receptors expressed by olfactory bulb neurons in primary culture, using electrophysiological techniques to focus on their role in synaptic transmission.

初级突触回路遍及大多数CNS，包括 嗅球，使用氨基酸递质，包括谷氨酸，GABA， 和甘氨酸。 尽管在表征这些方面取得了进展， 电路，很少有人知道他们的调制内源性 神经活性物质 考虑到氨基酸的公认作用 突触可塑性和某些形式的神经病理学中的递质， 内源性氨基酸受体的调节是可能的， 物质影响这些过程。 因此，必须澄清 这种调节的机制。 过渡金属锌和铜代表内源性神经活性 这些物质高度集中在灯泡中。因为这些 过渡金属已被证明是由神经元释放在其他 CNS的区域，有人提出，它们的功能是 突触传递过程中的神经调节剂。此外该 锌和（或）铜在几种神经病理状态中意义 (Pick的疾病、威尔逊氏病、癫痫和阿尔茨海默氏病） 表明这些金属可能与异常调制有关 氨基酸传递器的突触通路。 这一假设 进一步得到了试验数据的支持，这些数据表明氨基的调节 锌和铜的酸介导电流。 沿着锌和铜，二肽肌肽也存在于 嗅觉系统 尽管它已被提议作为发射机或 调制器，试图验证这一假设产生了模棱两可的 结果 然而，嗅觉感觉神经元含有 锌，肌肽，谷氨酸，表明潜在的联合 在神经调节中的作用我们的试验数据表明肌肽 调节锌和铜对氨基酸受体的作用， 嗅球神经元也与这种可能性相一致。 特征鲜明的回路和丰富的神经活性物质 这些物质使哺乳动物的嗅球成为 研究神经调节 此外，嗅觉功能障碍是一种 几种神经病理状况的早期表现 与衰老（例如帕金森病，阿尔茨海默病）， 被认为与氨基酸递质病理学有关。 本提案的目的是探索锌的调节作用， 铜和肌肽对表达的NMDA、GABAA和甘氨酸受体的影响 原代培养嗅球神经元，采用电生理 技术，专注于他们在突触传递中的作用。