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

大脑接收来自感觉器官(如耳朵)的信号，并对其进行处理，以提取关于世界的信息。输入的信号是被称为动作电位(AP)的电脉冲的形式。它们的幅度约为0.1伏，持续时间约为1毫秒。AP沿着神经传播，在被称为突触的特殊连接上释放脑细胞(神经元)之间的化学信使。这种信号的大部分是由称为离子通道的蛋白质完成的。这些蛋白质由亚基组成，每个亚基由一个基因指定。神经元必须将所有这些蛋白质组装成分子机器以进行信号传递。我的实验室专注于一类被称为“钾通道”的电压门控离子通道，它有80多个基因。这些钾通道是所有其他形式的兴奋性建立的基础，它们有助于抑制一个信号后的兴奋性，从而使神经元为下一个信号做好准备。神经元控制其钾通道的机制(S)对大脑功能和意识是基本的：钾通道的活动太少，大脑就会癫痫，太多，我们就会变得紧张症。这笔拨款将探索两个钾通道家族的调节机制(一个称为Kv3的电压门控家族，有四个成员(Kv3.1-3.4)和一个泄漏(或通量门控)钾通道家族，称为两孔或K2P通道。大多数对钾通道的研究是在细胞系中完成的，但为了了解它们的功能，研究必须在实际大脑中的真实神经元中进行；因此，我们在体外工作，研究来自人类死亡小鼠的脑组织。这些离子通道与人类的离子通道几乎相同。我们可以测量大脑的活动并操纵钾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力和大脑。这是因为倾听需要快速处理和极高的精度来整合来自两只耳朵的信息，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(在酒吧听对话)。我的实验室在通道和听觉科学方面有丰富的经验。钾通道亚单位有80多个基因，所以我们致力于一个被称为Kv3(钾通道家族3)的家族中的4个基因的子集。关键是，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Kv3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单位对声音处理如此关键，并了解突变是如何导致疾病的。Kv3.3的突变也会导致小脑一种名为脊髓小脑性共济失调13(SCA13)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，对理解与年龄相关的听力损失也很重要，这可能反过来与理解神经元在痴呆中死亡的原因有关。

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.