Subunit specific mechanisms by which potassium channels mediate intrinsic plasticity and neuronal integration in the auditory pathway

钾通道介导听觉通路内在可塑性和神经元整合的亚基特异性机制

• 批准号: BB/R001154/1
• 负责人: Ian Forsythe
• 金额: $ 91.81万
• 依托单位: University of Leicester
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FR001154%2F1
• 关键词: Subunit; specific; mechanisms; potassium; channels

The brain receives signals from sense organs (such as the ear) and processes it to extract information about the world. The incoming signals are in the form of electric pulses called 'action potentials' (APs). They are around 0.1 Volts in amplitude and 1 millisecond in duration. The APs propagate along nerves to release chemical messengers between brain cells (neurons) at specialized connections known as synapses. Much of this signalling is done by proteins called ion channels. These proteins are built from subunits each specified by a gene. Neurons must assemble all these proteins into molecular machines for signalling. My lab focusses on one class of voltage-gated ion channels called "potassium channels", for which there are over 80 genes. These potassium channels are the foundation on which all other forms of excitability are built, and they help to dampen the excitability after one signal, so that neurone is ready for the next.The mechanism(s) by which the neurons control their potassium channels are fundamental for brain function and consciousness: too little activity of potassium channels and the brain goes epileptic, too much and we are become catatonic. This grant will explore the mechanisms by which two families of potassium channels are regulated (a voltage-gated family called Kv3 of which there are four members (Kv3.1-3.4) and a family of leak (or flux-gated) potassium channels called two-pore or K2P channels.Most studies of potassium channels are done in cell lines, but to understand their function, studies must be conducted in real neurons within an actual brain; hence we work in vitro, on tissue from the brains of humanely killed mice. These ion channels are nearly identical to those of humans. We can measure the brain activity and manipulate the potassium channels to test their contribution to specific tasks.Our model system for this study is hearing and the brain. This is because listening requires fast processing and extreme precision in integrating information from both ears, so as to map sound objects and identify external threats (the sound of a car) or extract information from noisy environments (listening to a conversation in a bar). My laboratory has extensive experience of channel and auditory science.There are over 80 genes for potassium channel subunits, so we work on a subset of 4 genes in a family known as Kv3 (potassium channel family three). Crucially, only two of these genes are expressed in the auditory brainstem, and we have transgenic knockout mice for both genes. We are most interested in the third gene of the Kv3 family (Kv3.3) as mutations of this gene are linked to hearing disorders. We aim to discover why these channel subunits are so crucial for sound processing and to understand how mutations can produce disease. A mutation in Kv3.3 also causes a form of neurodegeneration in the cerebellum called spinocerebellar ataxia 13 (SCA13), so we anticipate that our basic science results will help understand mechanisms of hearing and also be important for understanding age-related hearing loss, which may in turn be relevant to understanding why neurons die in dementia.

大脑接收来自感觉器官（如耳朵）的信号，并对其进行处理以提取有关世界的信息。传入的信号是以电脉冲的形式，称为“动作电位”（AP）。它们的振幅约为0.1伏，持续时间约为1毫秒。AP沿着沿着神经传播，在称为突触的专门连接处释放脑细胞（神经元）之间的化学信使。这些信号大部分是由称为离子通道的蛋白质完成的。这些蛋白质是由基因指定的亚基组成的。神经元必须将所有这些蛋白质组装成信号分子机器。我的实验室专注于一类称为“钾离子通道”的电压门控离子通道，它有80多个基因。这些钾离子通道是所有其他形式的兴奋性的基础，它们有助于抑制一个信号后的兴奋性，以便神经元为下一个信号做好准备。神经元控制钾离子通道的机制是大脑功能和意识的基础：钾离子通道活动太少，大脑会癫痫，太多，我们会变得紧张症。该基金将探索两个钾通道家族的调节机制（称为Kv 3的电压门控家族，其中有四个成员（Kv3.1-3.4）和泄漏家族，钾通道（或通量门控）称为双孔或K2 P通道。大多数钾通道的研究都是在细胞系中进行的，但为了了解它们的功能，研究必须在实际大脑中的真实的神经元中进行，因此我们在体外工作，在人类杀死的老鼠的大脑组织上进行。这些离子通道与人类的几乎相同。我们可以测量大脑的活动并操纵钾离子通道来测试它们对特定任务的贡献。我们这项研究的模型系统是听觉和大脑。这是因为倾听需要快速处理和极高的精度来整合双耳的信息，以便映射声音对象并识别外部威胁（汽车的声音）或从嘈杂的环境中提取信息（听酒吧里的对话）。我的实验室在通道和听觉科学方面有着丰富的经验。钾通道亚基有80多个基因，因此我们研究了Kv 3家族（钾通道家族3）中的4个基因。最重要的是，这些基因中只有两个在听觉脑干中表达，我们有两个基因的转基因敲除小鼠。我们最感兴趣的是Kv 3家族的第三个基因（Kv3.3），因为该基因的突变与听力障碍有关。我们的目标是发现为什么这些通道亚基对声音处理如此重要，并了解突变如何产生疾病。Kv3.3的突变也会导致小脑中一种称为脊髓小脑共济失调13（SCA 13）的神经变性，因此我们预计我们的基础科学结果将有助于理解听力机制，对于理解与年龄相关的听力损失也很重要，这反过来可能与理解为什么神经元在痴呆症中死亡有关。

项目成果

Kv3.3 subunits control presynaptic action potential waveform and neurotransmitter release at a central excitatory synapse.

• DOI: 10.7554/elife.75219
• 发表时间: 2022-05-05
• 期刊: ELIFE
• 影响因子: 7.7
• 作者: Richardson, Amy;Ciampani, Victoria;Stancu, Mihai;Bondarenko, Kseniia;Newton, Sherylanne;Steinert, Joern R.;Pilati, Nadia;Graham, Bruce P.;Kopp-Scheinpflug, Conny;Forsythe, Ian D.
• 通讯作者: Forsythe, Ian D.

Kv3.3 subunits control presynaptic action potential waveform and neurotransmitter release at a central excitatory synapse

Kv3.3 亚基控制中枢兴奋性突触的突触前动作电位波形和神经递质释放

• DOI: 10.1101/2021.11.02.466934
• 发表时间: 2021
• 作者: Richardson A