Activity-dependent regulation of synaptic strength and cellular mechanisms of migraine

突触强度的活动依赖性调节和偏头痛的细胞机制

• 批准号: MR/M013812/1
• 负责人: Kirill Volynski
• 金额: $ 69.82万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FM013812%2F1
• 关键词: Activity; dependent; regulation; synaptic; strength

Migraine is a chronic neurological disorder where affected patients experience recurrent attacks of moderate to severe headaches that are often accompanied by other debilitating symptoms such as nausea, vomiting and sensitivity to light, smell, or sound. Migraine affects over 10% of the population and represents a major disease burden for society. The neuronal mechanisms of this syndrome remain however poorly understood.Some inherited cases of migraine, as well as other episodic neurological disorders such as ataxia (incoordination due to abnormal cerebellar function) and epilepsy, are caused by mutations of ion channels that gate calcium, sodium, or potassium fluxes across presynaptic membranes during action potentials. These "presynaptic neurological channelopathies" are thought to destabilise neuronal networks by affecting the release of neurotransmitters. The effects of the disease mutations on the channel functions in channelopathies can be precisely determined by electrophysiological methods. Therefore, understanding the mechanisms of channelopathies provides invaluable insights into the pathogenesis of more common forms of migraine, ataxia and epilepsy.The conventional way to study channelopathies is to determine the precise effects of a mutation at the single channel level and then to relate these effects to changes in synaptic transmission in neuronal models of disease. However, this straightforward approach often leads to paradoxical results. Using our pilot data we hypothesise that the missing key to understanding these diseases is homeostatic compensation of synaptic transmission, which, although abundantly documented in experimental studies, has been largely overlooked in studies of pathogenic mechanisms. Homeostatic synaptic plasticity is a negative feedback mechanism, which compensates for increases or decreases in neuronal activity by adjusting the strengths of innervating synapses. Our preliminary data argue that channelopathies do invoke homeostatic changes. Furthermore, an understanding of homeostatic compensation could go a long way to resolve the long-standing puzzle why most neurological channelopathies are episodic disorders, which generally do not interfere with brain function between manifestations of the disease.In this project we propose for the first time to systematically study the role of homeostatic mechanisms in channelopathies using mouse models of Familial Hemiplegic Migraine Type 1 (FHM1). FHM1 is caused by mutations in the CACNA1A gene that encodes the pore forming subunit of P/Q-type presynaptic calcium channels that are the major triggers of neurotransmitter release in the brain. We have recently developed a set of new imaging methods, which allow us to study the relationship between calcium entry and vesicular exocytosis, and to probe presynaptic ion channel function in individual small presynaptic terminals. Using these techniques we will determine to what extent the gain of function effects of two different FHM1 CACNA1A mutations (S218L and R192Q) are homeostatically compensated in different types of brain neuronal networks. This should provide first insights into the role and the limitations of homeostatic compensation for inherited ion channel dysfunction, which can be used as a novel framework to understanding the abnormal behaviour of neuronal circuits in paroxysmal neurological disorders. In a long term our results may identify new target mechanisms to prevent or mitigate the clinical manifestations of intermittent disturbances of synaptic transmission.

偏头痛是一种慢性神经疾病，受影响的患者反复发作中到重度头痛，通常伴随着其他令人衰弱的症状，如恶心、呕吐和对光、气味或声音敏感。偏头痛影响了10%以上的人口，是社会的主要疾病负担。然而，这种综合征的神经机制仍不清楚。一些遗传性偏头痛病例以及其他发作性神经疾病，如共济失调(由于小脑功能异常)和癫痫，是由离子通道的突变引起的，这些离子通道在动作电位期间控制钙、钠或钾的流动穿过突触前膜。这些“突触前神经通道病”被认为通过影响神经递质的释放而破坏神经元网络的稳定。疾病突变对经络病通道功能的影响可以通过电生理学方法精确地确定。因此，了解经络病变的机制对于更常见的偏头痛、共济失调和癫痫的发病机制提供了宝贵的见解。研究经络病变的传统方法是在单通道水平上确定突变的准确影响，然后将这些影响与神经元疾病模型中突触传递的变化联系起来。然而，这种直截了当的方法往往会导致自相矛盾的结果。利用我们的试点数据，我们假设，理解这些疾病所缺少的关键是突触传递的动态平衡补偿，尽管在实验研究中有大量的记录，但在致病机制的研究中基本上被忽视了。稳态突触可塑性是一种负反馈机制，它通过调节神经突触的强度来补偿神经元活动的增加或减少。我们的初步数据认为，通道病变确实会引发内环境平衡变化。此外，对稳态补偿的理解可能会在很长一段时间内有助于解决长期存在的难题，为什么大多数神经通道病都是发作性疾病，通常不会干扰疾病表现之间的大脑功能。在这个项目中，我们首次提出使用家族性偏瘫1型偏头痛(FHM1)的小鼠模型来系统地研究稳态机制在通道病中的作用。FHM1是由CACNA1A基因突变引起的，该基因编码P/Q型突触前钙通道的孔形成亚单位，该亚单位是大脑中神经递质释放的主要触发因素。我们最近开发了一套新的成像方法，使我们能够研究钙离子进入和囊泡吐出之间的关系，并探索单个小突触前终末的突触前离子通道功能。使用这些技术，我们将确定两个不同的FHM1 CACNA1A突变(S218L和R192Q)的功能效应增益在不同类型的脑神经网络中得到多大程度的稳态补偿。这应该提供了对遗传性离子通道功能障碍的稳态补偿的作用和局限性的初步见解，这可以作为一个新的框架来理解发作性神经疾病中神经元回路的异常行为。从长远来看，我们的结果可能确定新的靶向机制，以预防或减轻突触传递间歇性障碍的临床表现。

项目成果

Action potential broadening in a presynaptic channelopathy.

• DOI: 10.1038/ncomms12102
• 发表时间: 2016-07-06
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Begum R;Bakiri Y;Volynski KE;Kullmann DM
• 通讯作者: Kullmann DM

Low Stress Ion Conductance Microscopy of Sub-Cellular Stiffness.

• DOI: 10.1039/c6sm01106c
• 发表时间: 2016-10-14
• 期刊: Soft matter
• 影响因子: 3.4
• 作者: Clarke RW;Novak P;Zhukov A;Tyler EJ;Cano-Jaimez M;Drews A;Richards O;Volynski K;Bishop C;Klenerman D
• 通讯作者: Klenerman D

Lambert-Eaton syndrome IgG inhibits transmitter release via P/Q Ca2+ channels.

• DOI: 10.1212/wnl.0000000000001225
• 发表时间: 2015-02-10
• 期刊: Neurology
• 影响因子: 9.9
• 作者: Spillane J;Ermolyuk Y;Cano-Jaimez M;Lang B;Vincent A;Volynski KE;Kullmann DM
• 通讯作者: Kullmann DM

Action potential counting at giant mossy fiber terminals gates information transfer in the hippocampus.

巨型苔藓纤维末端的动作电位计数在海马中的信息传递。

• DOI: 10.1073/pnas.1720659115
• 发表时间: 2018-07-10
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Chamberland S;Timofeeva Y;Evstratova A;Volynski K;Tóth K
• 通讯作者: Tóth K

Action potential counting at giant mossy fiber terminals gates information transfer in the hippocampus

巨型苔藓纤维末端的动作电位计数控制了海马体的信息传递

• DOI: 10.1101/158444
• 发表时间: 2017
• 作者: Chamberland S