Targeting cotransmission for circuit-specific pharmacotherapy

针对回路特异性药物治疗的共传输

• 批准号: 10410440
• 负责人: STEPHEN RAYPORT
• 金额: $ 56.33万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10410440
• 关键词: Address; Adult; Affect; Amphetamines; Attenuated; Automobile Driving; Behavior; Behavioral; Biosensor; Blood - brain barrier anatomy; Brain; Chloride Channels; Corpus striatum structure; Development; Dopamine; Enzymes; Frequencies; Genetic; Glutamates; Glutaminase; Heterogeneity; Interneurons; Maps; Medial; Modeling; Mus; Neurons; Neurotransmitters; Nucleus Accumbens; Pharmacology; Pharmacotherapy; Phase; Phenotype; Reporting; Research; Role; Running; Schizophrenia; Signal Transduction; Slice; Symptoms; Synapses; Testing; Therapeutic; base; cholinergic; dopaminergic neuron; gamma-Aminobutyric Acid; glutamatergic signaling; inhibitor; novel; optogenetics; psychostimulant; transmission process

Dopamine neuron synapses — like most CNS synapses — release more than one neurotransmitter, with roles that extend from development, to trophic support to more nuanced signaling. Dopamine neurons release glutamate as a cotransmitter. Glutamate cotransmission confers striking heterogeneity to the synaptic actions of dopamine neurons across their principal target neurons in the striatum. Tempering dopamine neuron glutamate cotransmission by conditional reduction of the glutamate synthesizing enzyme glutaminase, encoded by Gls1, reduces dopamine neuron glutamate cotransmission at phasic firing frequencies. Mice with a global heterozygous reduction of Gls1 show potentiated latent inhibition, and are less prone to psychostimulant sensitization, two behavioral effects involving aberrant salience attribution. Strikingly, these two phenotypes are seen in mice with a Gls1 reduction restricted to their dopamine neurons. The impact of the Gls1 reduction on dopamine neuron dependent behaviors runs counter to symptoms of schizophrenia, arguing for therapeutic potential. The subtlety of the reduction, affecting dopamine neuron glutamate cotransmission at phasic firing frequencies in the nucleus accumbens, identifies key circuitry involved in salience attribution. The driving hypothesis of this proposal is that dopamine neuron glutamate cotransmission is involved in salience attribution and that reducing cotransmission has therapeutic potential for schizophrenia pharmacotherapy. In this project, we will focus first on the synaptic impact of the Gls1 reduction on dopamine neuron dopamine and glutamate release (Aim 1), recording in cholinergic interneurons that respond to both transmitters, and in striatal projection neurons made into dopamine biosensors by expression of the dopamine-gated chloride channel LGC-53, enabling comparison of the differential impact of the Gls1 reduction on DA and GLU signals. Then, using an INTRSECT strategy (Aim 2), we will identify striatal dopamine neuron projections capable of glutamate cotransmission, and use optogenetic stimulation to examine their role in salience attribution. Finally, we will test glutaminase inhibition pharmacotherapy (Aim 3) showing first in brain slices that genetic reduction of Gls1 and pharmacological inhibition of glutaminase similarly and preferentially impact dopamine neuron glutamate cotransmission, and then induce a global Gls1 reduction in adulthood modeling pharmacotherapy to show the behavioral impact. Finally, we will make a dopamine neuron-selective Gls1 reduction in adulthood to evaluate both the synaptic and behavioral impact. This research should increase understanding of the role of dopamine neuron glutamate cotransmission and advance therapeutics based on activity dependent modulation of glutamate release, specifically glutaminase inhibition as a novel pharmacotherapy for schizophrenia.

多巴胺神经元突触-像大多数中枢神经系统突触-释放一种以上的神经递质， 从发育到营养支持再到更微妙的信号传递。多巴胺神经元 释放谷氨酸作为共递质。谷氨酸共传递赋予了细胞惊人的异质性 纹状体中多巴胺神经元跨越其主要靶神经元的突触作用。回火 多巴胺神经元通过条件性还原谷氨酸合成酶的谷氨酸共传递 Gls 1编码的谷氨酰胺酶减少多巴胺神经元谷氨酸在时相放电时的共传递 频率. Gls 1整体杂合减少的小鼠显示出增强的潜伏性抑制， 不太容易产生精神刺激敏感，这两种行为效应涉及异常的显著性归因。 引人注目的是，这两种表型在Gls 1减少仅限于多巴胺的小鼠中观察到。 神经元Gls 1减少对多巴胺神经元依赖性行为的影响与 精神分裂症的症状，认为有治疗潜力。减少的微妙之处，影响 多巴胺神经元谷氨酸共传递在脑桥核中的相位放电频率， 识别了涉及显著性归因的关键电路。这一提议的主要假设是， 多巴胺神经元谷氨酸共传递参与显著性归因， 共传递对精神分裂症药物治疗具有治疗潜力。在这个项目中，我们将 首先关注Gls 1减少对多巴胺神经元多巴胺和谷氨酸的突触影响 释放（目的1），记录在胆碱能中间神经元，响应这两个递质，并在纹状体 通过表达多巴胺门控氯离子通道使投射神经元成为多巴胺生物传感器 LGC-53，能够比较Gls 1减少对DA和GLU信号的差异影响。然后， 使用INTRSECT策略（目标2），我们将识别纹状体多巴胺神经元投射， 谷氨酸共传递，并使用光遗传学刺激来检查它们在显著性归因中的作用。 最后，我们将测试转氨酶抑制药物疗法（Aim 3），首先在脑切片中显示，遗传 Gls 1的减少和转氨酶的药理学抑制类似地且优先地影响 多巴胺神经元谷氨酸共传递，然后诱导成年期模型的全局Gls 1减少 药物治疗对行为的影响。最后，我们将使多巴胺神经元选择性Gls 1 减少成年期，以评估突触和行为的影响。这项研究应该增加 了解多巴胺神经元谷氨酸共传递的作用和基于 对谷氨酸释放的活性依赖性调节，特别是作为一种新的 精神分裂症的药物治疗