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（与大多数CNS突触一样），释放多个神经递质，具有 从发育到营养支持到更细微的信号传导的角色。多巴胺神经元 将谷氨酸释放为共晶剂。谷氨酸共晶承认引人注目的异质性 多巴胺神经元在其主要靶神经元中的突触作用。回火 多巴胺神经元谷氨酸共转移通过谷氨酸合成酶的有条件还原 由GLS1编码的谷氨酰胺酶减少了阶段性射击时多巴胺神经谷氨酸共转移 全球杂合减少GLS1的小鼠显示潜在的潜在抑制作用，并且是 不太容易发生敏感性，两种涉及异常显着属性的行为效应。 令人惊讶的是，这两种表型在将GLS1还原限制为多巴胺的小鼠中看到 神经元。 GLS1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，主张治疗潜力。减少的微妙之处，影响 多巴胺神经元谷氨酸共转移在伏伏核中的阶段性射击频率， 标识与显着性属性有关的关键电路。该提议的驾驶假设是 多巴胺神经元谷氨酸共晶涉及显着属性，并减少 共晶具有精神分裂症药物疗法的治疗潜力。在这个项目中，我们将 首先关注GLS1减少对多巴胺神经多巴胺和谷氨酸的突触影响 释放（AIM 1），在胆碱能中间神经元中录制，以响应两种发射机，并在纹状体中记录 通过表达多巴胺门控氯化物通道，投射神经元成为多巴胺生物传感器 LGC-53，可以比较GLS1降低对DA和GLU信号的差异影响。然后， 使用统治策略（AIM 2），我们将确定能够的纹状体多巴胺神经元项目 谷氨酸共转移，并使用光遗传刺激来检查其在显着属性中的作用。 最后，我们将测试谷氨酰胺酶抑制药物疗法（AIM 3）在脑切片中首先显示遗传 类似地降低了GLS1和药物抑制谷氨酰胺酶，最好影响 多巴胺神经元谷氨酸共晶，然后诱导全局GLS1减少成年模型 药物治疗以显示行为影响。最后，我们将制作多巴胺神经选择性GLS1 减少成年期，以评估突触和行为影响。这项研究应该增加 了解多巴胺神经元谷氨酸共晶和基于预先治疗的作用 关于谷氨酸释放的活动依赖性调制，特别是谷氨酰胺酶抑制作用 精神分裂症的药物治疗。