Regulation of the striatal network by glutamate and acetylcholine co-transmission.

谷氨酸和乙酰胆碱共同传递对纹状体网络的调节。

• 批准号: RGPIN-2017-04682
• 负责人: ElMestikawy, Salah
• 金额: $ 1.82万
• 依托单位: McGill University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=710765
• 关键词: Regulation; striatal; network; glutamate; acetylcholine

Neurons communicate with electrochemical signals. Chemical messengers, or neurotransmitters, are accumulated inside synaptic vesicles (SV) before their calcium-dependent release. Glutamate (glut) the major excitatory transmitter in the brain is concentrated inside SV by vesicular transporter named VGLUT1-3. Our team made the surprising discovery that VGLUT3 is expressed by neurons using other neurotransmitters than glutamate. VGLUT3 is present used by all striatal cholinergic interneurons (also named Tonically Active Neurons or TANS). Therefore, TANS signal with both acetylcholine (ACh) and glut. The consequences of ACh/glut cotransmission recently started to be investigated. For example, we established that VGLUT3 null mice are hyperactive and more sensitive to cocaine. This is essentially due to an increased dopamine signaling in the nucleus accumbens in the absence of VGLUT3. Interestingly, silencing ACh signaling in TANS by specific ablation of the vesicular ACh transporter (VAChT) has opposite effects. Therefore, the dual ACh/glut transmission provides TANS with complex regulatory properties of striatal networks. We recently observed that VAChT or VGLUT3 are sorted to different populations of SVs in TANS. The objective of our proposal is to better understand molecular mechanisms underlying the vesicular sorting of VAChT or VGLUT3 in TANS. This will help to identify original molecular targets involved in the regulation of striatal networks. In particular, different types of calcium channels (L, N, P, and Q channels) critically regulate neurotransmitter release. These calcium channels have different kinetics properties and are often coupled to either single spike or bursting activity of neurons. In addition, nothing is known on how VGLUT3 and VAChT influence each other vesicular sorting. In this context, we propose 2 major tasks: i) to identify which synaptic proteins such as synaptotagmins or calcium channels associated with VAChT- or VGLUT3-positive SVs and ii) to clarify how VAChT or VGLUT3 impact on each other synaptic targeting. The major outcome of this research will be a better understanding of TANS, a pivotal neuronal population with unique properties. This knowledge will fuel research on striatal functions such as locomotor activity, habits- or reward-guided behaviors. Therefore pathologies as diverse as Parkinson's disease, obsessive-compulsive disorders or addiction could benefits from basic knowledge that will emerge from our investigations.

神经元通过电化学信号进行交流。化学信使或神经递质在其钙依赖性释放之前积聚在突触囊泡（SV）内。谷氨酸（glut）是脑内主要的兴奋性递质，通过称为VGLUT 1 -3的囊泡转运蛋白集中在SV内。我们的团队做出了令人惊讶的发现，VGLUT 3是由神经元使用其他神经递质而不是谷氨酸表达的。VGLUT 3被所有纹状体胆碱能中间神经元（也称为紧张性活性神经元或TNS）使用。因此，TANS信号与乙酰胆碱（ACh）和glut。ACh/过量共传递的后果最近开始调查。例如，我们确定VGLUT 3缺失小鼠是过度活跃的，对可卡因更敏感。这基本上是由于在VGLUT 3不存在的情况下，丘脑核中多巴胺信号传导增加。有趣的是，沉默乙酰胆碱信号在TANS特异性消融囊泡乙酰胆碱转运蛋白（VAChT）有相反的效果。因此，ACh/glut的双重传递为TANS提供了纹状体网络的复杂调节特性。 我们最近观察到，VAChT或VGLUT 3在TANS中被分选到不同的SV群体。我们的建议的目的是更好地了解分子机制的VAChT或VGLUT 3的囊泡分选在TANS。这将有助于确定参与纹状体网络调控的原始分子靶点。特别是，不同类型的钙通道（L，N，P和Q通道）严格调节神经递质的释放。这些钙通道具有不同的动力学特性，并且通常与神经元的单个锋电位或爆发活动偶联。此外，还不知道VGLUT 3和VAChT如何相互影响囊泡分选。 在这种情况下，我们提出了2个主要任务：i）确定哪些突触蛋白，如突触结合蛋白或钙通道与VAChT或VGLUT 3阳性SV和ii）澄清VAChT或VGLUT 3如何影响彼此的突触靶向。 这项研究的主要成果将是更好地了解TANS，这是一个具有独特特性的关键神经元群体。这些知识将推动对纹状体功能的研究，如运动活动，习惯或奖励引导的行为。因此，帕金森氏病、强迫症或成瘾等多种病理学都可以从我们的调查中获得的基本知识中受益。