Intrinsic plasticity of neuronal excitability in the auditory brainstem and neocortex: nitrergic signalling to voltage-gated potassium channels

听觉脑干和新皮质神经元兴奋性的内在可塑性：电压门控钾通道的氮能信号传导

• 批准号: MR/K005170/1
• 负责人: Ian Forsythe
• 金额: $ 88.22万
• 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: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FK005170%2F1
• 关键词: Intrinsic; plasticity; neuronal; excitability; auditory

Many people suffer from brain diseases caused by over-excitability (e.g. tinnitus, epilepsy or attention deficit hyperactivity disorder) exemplifying a fundamental problem: How does the brain keep a balance between too much and too little activity (e.g. epilepsy vs coma)? Maintaining this balance or equilibrium is known as "Homeostasis" (like keeping the correct body temperature: too hot or too cold is bad for you). In the brain too an imbalance of activity is associated with disease and dementia.Brain cells (neurons) receive information from their neighbours via chemical messengers (neurotransmitters) released at specialised contacts called synapses. We know a lot about how synapses work: excitatory synapses release a messenger called glutamate and this excites the target neuron to trigger an electrical pulse (action potential, AP). This AP then propagates along the neuronal process (axon) to the next set of synapses on other neurons. Thus networks of interconnected neurons pass information to each other; neurons use electrical pulses for internal information transmission and chemical messengers at synapses to communicate with each other. If a neuron receives lots of synapses then it should fire many APs, and scientists have shown that changing the strength of the synapses (giving more or less excitation) underlies learning and memory - this is often called synaptic plasticity. But how does a neuron know when to fire an AP? The action potential is generated by a class of proteins known as Voltage-Gated Ion Channels: sodium channels start the AP and potassium channels terminate it. Potassium channels are crucial regulators of neuronal excitability; they determine when it fires APs, how many it fires and how long they last. There are around 40 genes specifying different potasium channels, so they are difficult to study in 'real' neurons. The summed activity of all ion channels in a neuron determines its "intrinsic excitability" and changes in this are called "intrinsic plasticity" (in analogy with synaptic plasticity). So the brain can modify synaptic strength by a process of synaptic plasticity and adjust its ability to fire APs by changing intrinsic plasticity. Although scientists know a lot about synaptic plasticity, intrinsic plasticity has only recently been recognised as playing a significant role.We have shown that one messenger for this intrinsic plasticity is the chamical nitric oxide (NO). NO has many physiological roles in the immune, cardiovascular, reproductive and alimentary systems. NO acts on its receptor, guanylyl cyclase to generate cGMP and activates protein kinase G (PKG). These and other kinases change protein structure, activity or trafficking by adding phosphate groups.My laboratory has studies two channel families called Kv2 and Kv3 (KvX - stands for voltage-gated potassium channel family 2 or 3, respectively). These channels 'pull' the voltage back down to the resting voltage (around -70mV) after an AP so as to prepare the neuron for the next AP. We have discovered that an excitatory synaptic messenger (glutamate) causes some neurons to make NO and this signals to surrounding neurons to change from using Kv3 to Kv2 channels; i.e. the synapse has triggered intrinsic plasticity. We have spent 6 years tacking down how this is achieved at one type of synapse in the auditory pathway. Recently we showed that the same process is occurring in the hippocampus (which is the old part of the neocortex). We have developed many molecular tools and are now ready to determine the broader significance of this phenomenon for cortical function (using that part concerned with hearing - the auditory cortex) and how it contributes to disease and injury processes such as deafness (in the auditory brainstem) and tinnitus or epilepsy in the higher brain areas.Our work is an example of how fundamental research is necessary to understand mechanisms of disease.

许多人患有由过度兴奋引起的脑部疾病（例如耳鸣，癫痫或注意缺陷多动障碍），这说明了一个基本问题：大脑如何在过多和过少的活动之间保持平衡（例如癫痫与昏迷）？保持这种平衡或平衡被称为“稳态”（就像保持正确的体温：太热或太冷对你不好）。在大脑中，活动的不平衡也与疾病和痴呆症有关，脑细胞（神经元）通过在称为突触的专门接触点释放的化学信使（神经递质）从邻居那里接收信息。我们知道很多关于突触如何工作：兴奋性突触释放一种叫做谷氨酸的信使，这会刺激目标神经元触发电脉冲（动作电位，AP）。然后，该AP沿着神经元突起（轴突）传播到其他神经元上的下一组突触。因此，相互连接的神经元网络相互传递信息;神经元使用电脉冲进行内部信息传输，并在突触处使用化学信使进行相互通信。如果一个神经元接收到大量的突触，那么它应该激发许多AP，科学家已经证明，改变突触的强度（给予或多或少的兴奋）是学习和记忆的基础-这通常被称为突触可塑性。但是神经元如何知道何时发射AP呢？动作电位是由一类称为电压门控离子通道的蛋白质产生的：钠通道启动AP，钾通道终止AP。钾通道是神经元兴奋性的关键调节器;它们决定何时激活AP，激活多少AP以及持续多长时间。大约有40个基因指定不同的钾通道，因此很难在“真实的”神经元中研究它们。神经元中所有离子通道的活性总和决定了其“内在兴奋性”，这种变化被称为“内在可塑性”（与突触可塑性类似）。因此，大脑可以通过突触可塑性的过程来改变突触的强度，并通过改变内在可塑性来调整其激活AP的能力。虽然科学家们对突触可塑性了解很多，但内在可塑性直到最近才被认为起着重要的作用。我们已经证明，这种内在可塑性的一个信使是查米卡尔（NO）。NO在免疫、心血管、生殖和消化系统中具有多种生理作用。NO作用于其受体鸟苷酸环化酶产生cGMP并激活蛋白激酶G（PKG）。这些激酶和其他激酶通过添加磷酸基团来改变蛋白质结构、活性或运输。我的实验室研究了两个称为Kv 2和Kv 3的通道家族（KvX -分别代表电压门控钾通道家族2或3）。这些通道在AP后将电压“拉”回到静息电压（约-70mV），以便为下一个AP准备神经元。我们已经发现，兴奋性突触信使（谷氨酸）导致一些神经元产生NO，并向周围神经元发出信号，从使用Kv 3通道变为Kv 2通道;即突触触发了内在可塑性。我们花了6年时间来研究听觉通路中的一种突触是如何实现这一点的。最近，我们发现同样的过程也发生在海马体（新皮层的旧部分）中。我们已经开发了许多分子工具，现在准备确定这种现象对皮质功能的更广泛意义（使用与听力有关的部分-听觉皮层）以及它如何导致疾病和损伤过程，如耳聋（在听觉脑干）以及耳鸣或癫痫在更高的大脑区域。我们的工作是一个例子，说明如何基础研究是必要的，以了解疾病的机制。

项目成果

Glucose and lactate as metabolic constraints on presynaptic transmission at an excitatory synapse.

葡萄糖和乳酸作为兴奋性突触突触前传递的代谢限制。

• DOI: 10.1113/jp275107
• 发表时间: 2018
• 期刊: The Journal of physiology
• 作者: Lucas SJ

Protection from Noise-Induced Hearing Loss by Kv2.2 Potassium Currents in the Central Medial Olivocochlear System

• DOI: 10.1523/jneurosci.5043-12.2013
• 发表时间: 2013-05-22
• 期刊: JOURNAL OF NEUROSCIENCE
• 影响因子: 5.3
• 作者: Tong, Huaxia;Kopp-Scheinpflug, Cornelia;Forsythe, Ian D.
• 通讯作者: Forsythe, Ian D.

Acoustic trauma slows AMPA receptor-mediated EPSCs in the auditory brainstem, reducing GluA4 subunit expression as a mechanism to rescue binaural function.

• DOI: 10.1113/jp271929
• 发表时间: 2016-07-01
• 期刊: The Journal of physiology
• 作者: Pilati N;Linley DM;Selvaskandan H;Uchitel O;Hennig MH;Kopp-Scheinpflug C;Forsythe ID
• 通讯作者: Forsythe ID

Size matters: formation and function of giant synapses.

大小很重要：巨型突触的形成和功能。

• DOI: 10.1113/jphysiol.2013.258954
• 发表时间: 2013
• 期刊: The Journal of physiology
• 作者: Forsythe,IanD;Wu,Chunlai;Borst,JGerardG
• 通讯作者: Borst,JGerardG

Regulation of neuronal plasticity and fear by a dynamic change in PAR1-G protein coupling in the amygdala

• DOI: 10.1038/mp.2012.133
• 发表时间: 2013-10-01
• 期刊: MOLECULAR PSYCHIATRY
• 影响因子: 11
• 作者: Bourgognon, J-M;Schiavon, E.;Pawlak, R.
• 通讯作者: Pawlak, R.