PHARMACOLOGY OF MOSSY FIBER SYNAPATIC PLASTICITY

苔藓纤维突触可塑性的药理学

• 批准号: 3768284
• 负责人: DANIEL JOHNSTON
• 金额: --
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3768284
• 关键词: Alzheimer's disease; acetylcholine; alpha adrenergic receptor; beta adrenergic receptor; calcium channel; electrophysiology; hippocampus; laboratory rat; long term potentiation; membrane potentials; memory; molecular psychobiology; muscarinic receptor; neural facilitation; neural plasticity; neuropeptides; neuropharmacology; norepinephrine; voltage /patch clamp; zinc

Alzheimer's disease is characterized by a profound loss of memory. A number of neurotransmitter systems are reported to be diminished with the disease, including acetylcholine (ACh), norepinephrine (NE), dopamine, serotonin, certain opioid peptides, somatostatin, and substance P. Many of these neurotransmitters are likely to play a modulatory role in memory. Long term synaptic potentiation (LTP) is believed by many investigators to be a cellular substrate for elementary aspects of learning and memory. Recent work in our laboratory has shown that NE, ACh, and zinc modulate LTP at a particular excitatory synapse in the hippocampus, the mossy fiber synapse. It has been suggested that the activity of this synapse plays a role in amnesia or forgetting. Moreover, the mossy fiber pathway appears to be spared in Alzheimer's disease and may even shown some proliferation. A reasonable hypothesis would be that drugs that modulate long-term plasticity at this synapse might have some beneficial therapeutic effect in Alzheimer's disease. In fact, certain drugs (i.e., naloxone and aniracetam) that have been used to alleviate some symptoms of the disease have effects on LTP at this synapse. We propose to explore the mechanisms underlying the neuromodulation of mossy fiber LTP by the putative neurotransmitters NE and ACh. Furthermore, we propose to test the hypothesis that opioid peptides and zinc, which are both released from mossy fiber synapses and suggested to play a role in Alzheimer's disease and memory, contribute to the modulation of LTP at this synapse. We will utilize the in vitro hippocampal slice preparation and electrophysiological techniques, including intracellular current and voltage clamping, for our experimental studies. We believe that the results of our experiments will add significantly to our knowledge of the modulation of synaptic plasticity and hopefully will provide a basis for understanding the behavior of the whole animal.

阿尔茨海默病的特点是记忆力严重丧失。一个 据报道，神经递质系统的数量随着 该疾病，包括乙酰胆碱（ACh）、去甲肾上腺素（NE）、 多巴胺、血清素、某些阿片肽、生长抑素和 P 物质。许多神经递质可能发挥作用 对记忆的调节作用。长时程突触增强 (LTP) 是 许多研究人员认为它是基本的细胞基质 学习和记忆方面。我们实验室最近的工作表明 NE、ACh 和锌在特定的兴奋性突触处调节 LTP 在海马体中，苔藓纤维突触。有人建议 该突触的活动在健忘症或遗忘中发挥着作用。 此外，苔藓纤维通路似乎在阿尔茨海默病中幸免于难 疾病，甚至可能表现出某种增殖。合理的假设 是调节该突触长期可塑性的药物 可能对阿尔茨海默病有一些有益的治疗作用。在 事实上，某些已使用的药物（即纳洛酮和阿尼西坦） 缓解疾病的某些症状，此时对 LTP 有影响 突触。我们建议探索其背后的机制 假定的神经递质 NE 对苔藓纤维 LTP 的神经调节 和乙酰胆碱。此外，我们建议检验阿片类药物的假设 肽和锌，它们都是从苔藓纤维突触中释放出来的 建议在阿尔茨海默病和记忆中发挥作用，有助于 在此突触处调节 LTP。我们将利用体外 海马切片制备和电生理技术， 包括细胞内电流和电压钳位，对于我们 实验研究。我们相信我们的实验结果 将显着增加我们对突触调节的了解 可塑性，希望能为理解 整个动物的行为。