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

偏头痛是一种慢性神经系统疾病，其中受影响的患者经历中度至重度头痛的反复发作，通常伴有其他衰弱症状，如恶心，呕吐和对光，气味或声音敏感。偏头痛影响超过10%的人口，是社会的主要疾病负担。一些遗传性偏头痛病例以及其他偶发性神经系统疾病如共济失调（小脑功能异常引起的不协调）和癫痫，都是由动作电位过程中控制钙、钠或钾离子通过突触前膜的离子通道突变引起的。这些“突触前神经通道病”被认为是通过影响神经递质的释放来破坏神经网络的稳定。疾病突变对通道功能的影响可以通过电生理学方法精确地确定。因此，了解通道病的机制提供了宝贵的见解，更常见的偏头痛，共济失调和epilepse.The传统的方法来研究通道病的发病机制是确定在单通道水平的突变的精确效果，然后将这些影响与疾病的神经元模型中突触传递的变化。然而，这种直接的方法往往会导致矛盾的结果。使用我们的试点数据，我们假设，失踪的关键，以了解这些疾病是稳态补偿的突触传递，虽然在实验研究中有大量的记录，在很大程度上被忽视的致病机制的研究。稳态突触可塑性是一种负反馈机制，通过调节支配突触的强度来补偿神经元活动的增加或减少。我们的初步数据表明，通道病确实引起了体内平衡的变化。此外，了解稳态补偿可以走很长的路，以解决长期存在的难题，为什么大多数神经channelopathies是偶发性疾病，一般不干扰脑功能之间的表现diseases.In这个项目中，我们建议首次系统地研究稳态机制的作用，在channelopathies使用小鼠模型的家族性偏瘫偏头痛1型（FHM 1）。FHM 1是由CACNA 1A基因突变引起的，CACNA 1A基因编码P/Q型突触前钙通道的成孔亚基，而P/Q型突触前钙通道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，这使我们能够研究钙离子进入和囊泡胞吐之间的关系，并探测突触前离子通道功能在个别小突触前末梢。使用这些技术，我们将确定两种不同的FHM 1 CACNA 1A突变（S218 L和R192 Q）在不同类型的脑神经元网络中的稳态补偿的功能效应的增益在多大程度上。这应该提供第一个洞察的作用和局限性的遗传性离子通道功能障碍，这可以被用作一个新的框架，以了解异常行为的神经元回路在阵发性神经系统疾病的稳态补偿。从长远来看，我们的研究结果可能会发现新的靶点机制，以防止或减轻突触传递间歇性障碍的临床表现。

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.