In-vivo Modulation of Synapses by Endocannabinoids

这项研究的长期目标是研究内源性大麻素对突触的调节作用。 在中枢神经系统中的传播。实验模型包括已确定的混合电气和化学物质(谷氨酸能)。 第八神经听觉初级传入与金鱼Mauthner(M-)细胞及其邻近神经元的突触 (GABA/甘氨酸)抑制终末。虽然大多数研究都描述了内源性大麻素对突触的作用 传播利用了体外系统，这种制剂独特地允许连续监测和量化 体内电子和化学传递的变化。到目前为止，已有报道称内源性大麻素能抑制 化学突触传递通过突触前激活的大麻素1型受体(CBIR)。对比一下这个 我们的初步结果表明，CBIRs的激活增强了这些输入的突触传递。 M细胞。树突状细胞内录音、分子生物学技术和免疫细胞化学将用于检测 该激动剂引起突触传递改变的特定假说和机制。目标 1、探讨不同的大麻素激动剂和内源性大麻素对混合神经元突触效应的影响。 突触和抑制性终末。它基于的数据表明，CB1R的激活会导致长期持续 混合突触的电和化学传递的增强。这些变化还包括附近 抑制性终末。我将探索局部应用的大麻素激动剂和内源性大麻素对 与此功能相关的单一和群体突触反应和膜电导 听觉输入。目的2是研究这些突触传递的长期变化的机制。它 是基于多巴胺受体拮抗剂阻断CB1R激活引发的增强的发现。我们 以前曾报道过多巴胺能神经支配的存在和多巴胺诱发的持久应用 突触反应的增强。我们将检验这样一种假设，即大麻素诱发的增强作用是由 通过邻近静脉曲张的多巴胺释放。我们还会问，在什么生理条件下， 释放哪种特定的细胞类型的内源性大麻素。 这项拟议的研究解决了内源性大麻素对细胞间通讯的调制这一概念 不仅限于化学突触，还包括缝隙连接介导的电性突触。此外，基于 与多巴胺能系统的功能相互作用，它可以导致突触反应的长期增强。这 调制作用可能构成一种广泛的属性，不仅与大脑在这样的结构中的正常功能有关 作为基底节、视网膜和新皮质，这两种形式的传播共存，但也对许多健康- 与药物滥用等相关问题。

The long-term objective of the proposed research is to study the modulatory actions of endocannabinoids on synaptic transmission in the CNS. The experimental model involves identified mixed electrical and chemical, (glutamatergic) synapses between eighth nerve auditory primary afferents and the goldfish Mauthner (M-) cell and neighboring (GABA/Glycine) inhibitory terminals. While most studies describing the role of endocannabinoids on synaptic transmission have utilized in-vitro systems, this preparation uniquely allows continuous monitoring and quantification of changes in electrical and chemical transmission in-vivo. Sofar, endocannabinoids have been reported to depress chemical synaptic transmission via presynaptic activation of cannabinoid type 1 receptors (CBIRs). Contrasting this notion, our preliminary results show that activation ofCBIRs enhances synaptic transmission at these inputs on the M-cell. Intradendritic recordings, molecular biology techniques, and immunocytochemistry, will be used to test specific hypotheses and mechanisms underlying modifications of synaptic transmission induced by this agonist. Aim 1, explores the action of different cannabinoid agonists and endocannabinoids on the synaptic efficacy of mixed synapses and inhibitory terminals. It is based on data suggesting that activation of CB1R leads to long-lasting enhancement of both electrical and chemical transmission at mixed synapses. These changes also included nearby inhibitory terminals. I will explore the actions of locally applied cannabinoid agonists and endocannabinoids on unitary and population synaptic responses and membrane conductances that are relevant for the function of this auditory input. Aim 2 is to investigate the mechanisms underlying these long-term changes in synaptic transmission. It is based on the finding that dopamine receptor antagonists block the potentiation triggered by CB1R activation. We have previously reported the presence of a dopaminergic innervation and application of dopamine evoked lasting enhancements of the synaptic response. We will test the hypothesis that cannabinoid-evoked potentiation is mediated via dopamine release from neighboring varicosities. We will also ask under which physiological conditions and from which particular cell type endocannabinoids are released. The proposed research addresses the concept that modulation of intercellular communication by endocannabinoids is not restricted to chemical synapses but also include gap-junction mediated electrical synapses. Moreover, based on a functional interaction with the dopaminergic system, it can lead to long-term potentiation of synaptic responses. This modulatory action could constitute a widespread property, relevant not only to normal brain function in structures such as the basal ganglia, retina, and neocortex where both forms of transmission co-exist, but also to numerous health- related issues such as drug abuse.