Serotoninergic modulation of cerebellar circuitry

小脑回路的血清素能调节

• 批准号: 9899327
• 负责人: Kristin Palarz
• 金额: $ 2.28万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9899327
• 关键词: Activities of Daily Living; Acute; Affect; Amygdaloid structure; Area; Ataxia; Axon; Brain; Brain region; Cells; Cerebellar Cortex; Cerebellar Diseases; Cerebellum; Disease; Dose; Drug usage; Electrophysiology (science); Equilibrium; Eye; Fiber; Functional disorder; Future; G-Protein-Coupled Receptors; Goals; Hippocampus (Brain); Lead; Light; Machado-Joseph Disease; Maintenance; Motor; Movement; Neuromodulator; Neurons; Output; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Purkinje Cells; Receptor Activation; Research; Role; Serotonin; Serotonin Agonists; Serotonin Receptor 5-HT1A; Signal Pathway; Slice; Structure of purkinje fibers; Synapses; Synaptic Transmission; Testing; Therapeutic; Therapeutic Agents; Treatment Efficacy; clinically relevant; design; drug action; effective therapy; fiber cell; granule cell; improved; motor disorder; mouse model; patient subsets; receptor; serotonin 7 receptor; targeted treatment; therapeutic evaluation; therapeutic target

Project Summary/Abstract Ataxia (uncoordinated movement) is a debilitating disorder that interferes patients' ability to perform activities of daily living. Ataxia is caused by dysfunction of the cerebellum, a brain area involved in motor coordination and maintenance of balance. There are few therapies available for treatment of ataxia, and the ones used, such as serotoninergic agents, have limited efficacy often only in a subset of patients. Thus, there is a real need for new and improved therapeutic approaches for the management and treatment of ataxia. A major cause of cerebellar dysfunction is abnormal Purkinje cell activity. Purkinje cells, the sole output of the cerebellar cortex, are intrinsically active cells that integrate synaptic input from over 150,000 parallel fiber synapses and one climbing fiber. Serotonin (5-HT) has excitatory, inhibitory, or biphasic effects on firing rate of Purkinje cells. Similarly, serotonin depresses and potentiates parallel fiber-Purkinje cell synaptic transmission, and affects the climbing fiber-Purkinje cell synaptic transmission. The mechanisms by which serotonin causes these opposing effects are not understood. Nevertheless, because serotoninergic drugs are promising for the treatment of ataxia, it is important to delineate the mechanism by which they modulate cerebellar function. Serotoninergic drugs that have been most efficacious in lessening motor dysfunction were chosen to target the 5-HT1A receptor. However, these drugs can also activate 5-HT7 receptors. In the cerebellar cortex, 5-HT1A and 5-HT7 receptors are localized only to Purkinje cells and parallel fibers. Because 5-HT1A and 5-HT7 receptors typically have opposing effects on firing and synaptic transmission, it is plausible that the limited efficacy of serotoninergic drugs used to treat ataxia is due to activation of multiple receptors that elicit opposing effects on cerebellar function. Thus, in order to improve the therapeutics for ataxia, it is important to delineate how serotonin alters cerebellar function. The goal of this proposal is to elucidate how selective activation of 5-HT1A and 5-HT7 receptors alters Purkinje cell intrinsic firing and excitatory synaptic transmission onto Purkinje cells. To do so, this proposal uses electrophysiology to record from Purkinje cells in acutely prepared cerebellar slices. Aim 1 elucidates how selective 5-HT1A and 5-HT7 receptor activation affects Purkinje cell intrinsic firing. In addition, we will examine the therapeutic efficacy of selective serotonergic agonists that alter Purkinje cell activity in a mouse model of spinocerebellar ataxia type 3. Aim 2 delineates the effect of selective 5-HT1A and 5-HT7 receptor activation on parallel fiber and climbing fiber synaptic transmission, the pre- or post-synaptic components of any potential modulation, and long-term plasticity. Successful completion of this proposal will reveal the actions of clinically-relevant serotoninergic receptors and shed light on the regulatory role of the potent neuromodulator serotonin in the cerebellum. Furthermore, as we gain a better understanding of cerebellar function in different types of ataxia, and how serotonin modulates the cerebellar cortex, future studies will be better poised to design rational therapies to treat ataxia.

项目摘要/摘要 共济失调（不协调的运动）是一种令人衰弱的疾病，它会干扰患者的表现能力 日常生活的活动。共济失调是由小脑功能障碍引起的，小脑涉及电动机的大脑区域 平衡的协调和维护。没有可用于共济失调的疗法几乎没有疗法， 诸如5-羟色胺能剂等使用的患者通常仅在一部分患者中具有有限的疗效。因此，那里 真正需要对共济失调的管理和治疗进行新的和改进的治疗方法。 小脑功能障碍的主要原因是异常的浦肯野细胞活性。 Purkinje单元，唯一输出 小脑皮层的是本质上活跃的细胞，可整合超过150,000的突触输入 纤维突触和一个攀登纤维。 5-羟色胺（5-HT）对触发具有兴奋性，抑制性或双相作用 Purkinje细胞的速率。同样，5-羟色胺降低并增强平行纤维 - 棕榈蛋白细胞突触 传输，并影响攀爬纤维 - 纯棕榈孔细胞突触传播。所在的机制 血清素导致这些相反的作用尚不清楚。然而，因为5-羟色胺能药物是 有望治疗共济失调，重要的是要描述它们调节的机制 小脑功能。降低运动功能障碍最有效的5-羟色胺能药物是 被选为靶向5-HT1A受体。但是，这些药物也可以激活5-HT7受体。在 小脑皮层，5-HT1A和5-HT7受体仅定位于Purkinje细胞和平行纤维。因为 5-HT1A和5-HT7受体通常对发射和突触传播具有相反的影响，这是合理的 用来治疗共济失调的5-羟色胺能药物的有限疗效是由于多种受体的激活 这种对小脑功能产生了相反的影响。因此，为了改善共济失调的治疗剂 描述5-羟色胺如何改变小脑功能的重要性。该提议的目的是阐明 5-HT1A和5-HT7受体的选择性激活改变Purkinje细胞的内在触发和兴奋性突触 传播到Purkinje细胞上。为此，该建议使用电生理学记录来自Purkinje细胞的 明确准备的小脑切片。 AIM 1阐明了选择性的5-HT1A和5-HT7受体激活 影响浦肯野细胞的固有发射。此外，我们将研究选择性血清素能的治疗功效 在3型脊椎动物共济失调的小鼠模型中改变Purkinje细胞活性的激动剂。 选择性5-HT1A和5-HT7受体激活对平行纤维和攀爬纤维突触的影响 传输，任何潜在调制的突触前或突触后成分以及长期可塑性。 该提案的成功完成将揭示与临床相关的5-羟色胺能受体和 阐明了有效神经调节剂5-羟色胺在小脑中的调节作用。此外，正如我们一样 在不同类型的共济失调中更好地了解小脑功能，以及5-羟色胺如何调节 小脑皮层，未来的研究将更好地设计用于治疗共济失调的合理疗法。