Glycine receptor synaptic plasticity

甘氨酸受体突触可塑性

• 批准号: 9288232
• 负责人: Julie A. Kauer
• 金额: $ 42.31万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9288232
• 关键词: Abate; Adolescent; Animals; Area; Astrocytes; Auditory; Behavior; Behavioral; Behavioral Assay; Binding; Biochemical; Biotinylation; Brain; Brain Stem; Brain region; Cell Adhesion Molecules; Cells; Chemosensitization; Cultured Cells; Data; Development; Disease; Electrophysiology (science); Exhibits; Extracellular Matrix Proteins; Gated Ion Channel; Generations; Glycine; Glycine Receptors; Goals; Health; Human; Hyperalgesia; In Vitro; Inflammation; Inflammatory; Injury; Interleukin-1 Receptors; Interleukins; Ion Channel Gating; Knowledge; Ligands; Link; Long-Term Potentiation; Mediating; Methods; Microglia; Midbrain structure; Mission; Modification; Molecular; Motor; Mus; Nervous system structure; Neuraxis; Neuropathy; Neurotransmitters; Nociception; Pain; Pain Disorder; Pain Measurement; Pain management; Pathology; Peripheral; Pharmacologic Substance; Physiologic pulse; Posterior Horn Cells; Property; Protein Kinase; Public Health; Receptor Signaling; Reflex action; Regulation; Research; Research Proposals; Respiration Disorders; Retinal; Role; Signal Pathway; Signal Transduction; Slice; Source; Spinal Cord; Spinal Cord Diseases; Synapses; Synaptic Transmission; Synaptic plasticity; System; Testing; Tissues; Trauma; United States National Institutes of Health; Work; allodynia; base; chronic pain; cytokine; dorsal horn; experience; experimental study; in vivo; inflammatory pain; inhibitory neuron; innovation; motor disorder; new therapeutic target; novel strategies; postsynaptic; postsynaptic neurons; public health relevance; receptor; respiratory; response; scaffold; somatosensory; trafficking; transmission process; treatment strategy

DESCRIPTION (provided by applicant): Despite the great importance of glycine receptors in key areas of the nervous system with relevance for human health, remarkably little is known about the regulation of glycinergic synapse strength, and even less about glycinergic synapses in functional circuits. Glycinergic synapses comprise much of the inhibitory drive controlling networks in the spinal cord, brainstem and midbrain, regulating motor behavior, rhythm generation, somatosensory, auditory, and retinal signaling, and coordination of reflex responses. Our long-term goal is to understand how to control the strength of glycinergic synapses in the central nervous system to provide novel drug targets for disorders of spinal cord and brainstem circuits. The objective of this research proposal is to define how potentiation of glycinergic synapses is triggered and maintained, using functional studies in intact spinal cord slices from adolescent mice. Using electrophysiological recordings in spinal cord slices, we find that the inflammatory cytokine, IL-1beta, rapidly upregulates inhibitory glycine receptors on inhibitory neurons in the dorsal horn. To our knowledge, this is the first example of long-term potentiation (LTP) of glycine receptors anywhere in the CNS. The rapid inhibition of inhibitory dorsal horn neurons is expected to promote the transmission of pain signals to the brain, likely contributing to the known nociceptive effects of intrathecal IL-1beta. Our preliminary data support the hypothesis to be tested in this application: that IL-1beta released in the dorsal horn by peripheral injury activates cell adhesion molecules and intracellular protein kinase cascades, rapidly increasing synaptic glycinergic receptor numbers. The rationale for the proposed research is that by identifying the signaling cascades that normally control glycinergic synapse strength, we will provide novel therapeutic targets to treat pain and other glycine receptor-dependent disorders. Proposed experiments will elucidate the signaling pathways and receptor subtypes involved in glycinergic LTP (Aims 1 and 2), primarily relying on sensitive electrophysiological recordings in spinal cord slices. Our preliminary results also indicate that inflammation in vivo potentiates glycinergic synapses, similarly to IL-1beta potentiation observed in vitro. We will therefore identify the role of glycine receptor LTP after peripheral inflammation (Aim 3), using electrophysiological and behavioral assays. The proposed work is innovative, in our opinion, because 1) we have identified the first example of LTP at glycinergic synapses in the mammalian CNS, and 2) as synaptic plasticity can underlie pathology, delineating the underlying mechanisms offers a new way to control glycinergic synapses in disease. The contributions of this research will be the elucidation of as yet entirely unknown mechanisms underlying glycine receptor signaling and synaptic potentiation in a developed tissue setting. These contributions are significant because they constitute critical first steps towards the development of new treatments for pain, respiratory and motor disorders, and auditory disorders.

描述（由申请人提供）：尽管甘氨酸受体在与人类健康相关的神经系统的关键区域中非常重要，但对甘氨酸能突触强度的调节知之甚少，对功能回路中的甘氨酸能突触知之更少。甘氨酸能突触包括脊髓、脑干和中脑中的大部分抑制性驱动控制网络，调节运动行为、节律产生、躯体感觉、听觉和视网膜信号传导以及反射反应的协调。我们的长期目标是了解如何控制中枢神经系统中甘氨酸能突触的强度，为脊髓和脑干回路疾病提供新的药物靶点。本研究计划的目的是利用青少年小鼠完整脊髓切片的功能研究，确定甘氨酸能突触的增强是如何触发和维持的。利用脊髓切片的电生理记录，我们发现炎症细胞因子IL-1 β迅速上调背角抑制性神经元上的抑制性甘氨酸受体。据我们所知，这是中枢神经系统中甘氨酸受体长时程增强（LTP）的第一个例子。预期抑制性背角神经元的快速抑制可促进疼痛信号向大脑的传递，可能有助于鞘内IL-1 β的已知伤害性效应。我们的初步数据支持这一应用中待检验的假设：外周损伤在背角释放的IL-1 β激活细胞粘附分子和细胞内蛋白激酶级联，迅速增加突触甘氨酸能受体数量。这项研究的基本原理是，通过确定通常控制甘氨酸能突触强度的信号级联，我们将提供新的治疗靶点来治疗疼痛和其他甘氨酸受体依赖性疾病。拟议的实验将阐明参与甘氨酸能LTP的信号通路和受体亚型（目的1和2），主要依赖于脊髓切片中敏感的电生理记录。我们的初步结果还表明，体内炎症增强了甘氨酸能突触，类似于体外观察到的IL-1 β增强作用。因此，我们将确定甘氨酸受体LTP在外周炎症后的作用， (Aim 3），使用电生理和行为分析。在我们看来，这项工作是创新的，因为1）我们已经确定了哺乳动物中枢神经系统中甘氨酸能突触的第一个LTP的例子，2）突触可塑性可以作为病理学的基础，描绘潜在的机制提供了一种新的方法来控制疾病中的甘氨酸能突触。这项研究的贡献将是阐明尚未完全未知的机制，潜在的甘氨酸受体信号和突触增强在发达的组织设置。这些贡献是重要的，因为它们构成了开发疼痛、呼吸和运动障碍以及听觉障碍新疗法的关键的第一步。