MICA: The role of excitatory synaptic scaling in epileptogenesis in rodent and human brain networks

MICA：兴奋性突触缩放在啮齿动物和人类大脑网络癫痫发生中的作用

• 批准号: MR/W02036X/1
• 负责人: Gavin Woodhall
• 金额: $ 123.69万
• 依托单位: Aston University
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FW02036X%2F1
• 关键词: MICA; role; excitatory; synaptic; scaling

Brain cells are electrically excitable, meaning that they communicate with each other through tiny voltage 'spikes'. How likely a brain cell is to spike is related to how easily excitable it is. However, excitability of brain cells is not a static thing, it changes in response to recent activity, and we call this homeostatic scaling (HS). HS keeps brain cell spiking activity in a kind of special zone where the amount of excitation in brain cells is kept at just the right rate for them to 'talk' to each other without everyone talking at once.Epilepsy is a neurological (brain) disease which is characterised by seizures. Seizures are periods of time when networks of brain cells are too active and are uncontrollably excited and spiking. If uncontrolled excitation spreads to brain regions that control movement, then too many brain cells are 'talking at the same time' and we can see seizures as changes in movement such as jerks and twitches. The problem with our current treatment of epilepsy is that we can't stop seizures in as many as a third of people, and of the ones that we do treat successfully, about a third will stop responding to the drugs. If you add these two groups together, then about half of people with epilepsy are not being helped enough by their medication. Most of the drugs that are used in epilepsy aim to stop seizures from happening, and for this reason, they often work in similar ways and aim at the same targets in the brain. What is needed is a new approach, looking at how epilepsy establishes itself in vulnerable brain areas, and how we might be abel to stop this process from happening.Like brain excitability, epilepsy itself is not static, rather, it is an ever-changing process, where the excitability of brain cells and networks is altered by the epileptic seizures themselves. This means that the high activity of a seizure might drive down the excitability of the brain cells, as a kind of compensation that helps to prevent seizures in the short term. This kind of compensatory change happens through HS, just like in non-epileptic brains. We think this HS process goes wrong in epilepsy, overcompensating for seizure activity and making networks so 'quiet' that a process of re-compensation happens which makes individual brain cells start to become super-excitable. This project aims to test this idea by looking at how different amounts of epileptic activity in the brain can alter its excitability. In rats with implanted brain electrodes that broadcast brain activity using a Wi-Fi system, we will map how brain cells alter their excitability in response to seizures and how this change in spiking is related to how cells communicate via their thousands of synapses. We predict that if there are a lot of seizures, synapses will decrease their activity and brain cells will become more likely to spike. We will test antiepileptic drugs, and new drugs designed to interfere with HS to see if they can prevent seizures from developing or reduce their intensity. Finally, we will test this all in human brain, using samples of living tissue taken from children with difficult to treat epilepsies who have had to have some brain tissue removed to stop the seizures. The people in our project team are epilepsy specialists, epilepsy surgeons, molecular biologists and scientists from GW Pharma, the company responsible for the newest successful antoepilepsy drug, Epidiolex (CBD). Together, we are going to be able to make animal models of epilepsy processes, test that they happen in human brain and explore how new antiepileptic drugs can interfere in how epilepsy is established in the brain. Answers to these questions will mean that we can focus on making drugs that target the processes undelying epilepsy, modifying the disease itself instead of just stopping the symptoms. Our project will help future patients, clinicians treating epilepsy and providing scientists with new knowledge from which to further other projects.

脑细胞是电兴奋的，这意味着它们通过微小的电压“尖峰”相互交流。一个脑细胞出现尖峰的可能性与它的易兴奋性有关。然而，脑细胞的兴奋性不是一个静态的东西，它会随着最近的活动而变化，我们称之为稳态缩放（HS）。HS使脑细胞的尖峰活动保持在一种特殊的区域，脑细胞的兴奋程度保持在适当的速度，使它们能够相互“交谈”，而不需要每个人同时说话。癫痫是一种神经（大脑）疾病，其特征是癫痫发作。癫痫发作是脑细胞网络过于活跃，无法控制地兴奋和尖峰的时期。如果不受控制的兴奋扩散到控制运动的大脑区域，那么太多的脑细胞“同时说话”，我们可以将癫痫发作视为运动的变化，如抽搐和抽搐。我们目前治疗癫痫的问题是，我们无法阻止多达三分之一的人癫痫发作，而在我们成功治疗的人中，大约三分之一的人会停止对药物的反应。如果你把这两组加在一起，那么大约一半的癫痫患者没有得到足够的药物帮助。大多数用于癫痫的药物旨在阻止癫痫发作，因此，它们通常以相似的方式工作，并针对大脑中的相同目标。我们需要的是一种新的方法，研究癫痫是如何在脆弱的大脑区域建立起来的，以及我们如何能够阻止这一过程的发生。就像大脑的兴奋性一样，癫痫本身并不是静止的，相反，它是一个不断变化的过程，其中脑细胞和网络的兴奋性被癫痫发作本身改变。这意味着癫痫发作的高活动性可能会降低脑细胞的兴奋性，作为一种补偿，有助于在短期内防止癫痫发作。这种代偿性变化通过HS发生，就像在非癫痫大脑中一样。我们认为这种HS过程在癫痫中出错，过度补偿癫痫发作活动，使网络变得如此“安静”，以至于发生重新补偿的过程，使单个脑细胞开始变得超级兴奋。该项目旨在通过观察大脑中不同数量的癫痫活动如何改变其兴奋性来测试这一想法。在植入大脑电极的大鼠中，使用Wi-Fi系统广播大脑活动，我们将绘制脑细胞如何改变其兴奋性以响应癫痫发作，以及这种尖峰变化如何与细胞如何通过数千个突触进行通信有关。我们预测，如果癫痫发作次数很多，突触的活动会减少，脑细胞会变得更容易尖峰。我们将测试抗癫痫药物，以及旨在干扰HS的新药，看看它们是否可以防止癫痫发作或降低其强度。最后，我们将在人类大脑中测试这一切，使用从难以治疗癫痫的儿童身上提取的活组织样本，这些儿童不得不切除一些脑组织以阻止癫痫发作。我们项目团队的成员包括癫痫专家、癫痫外科医生、分子生物学家和GW Pharma的科学家，GW Pharma是负责最新成功的抗癫痫药物Epidiolex（CBD）的公司。总之，我们将能够制作癫痫过程的动物模型，测试它们是否发生在人类大脑中，并探索新的抗癫痫药物如何干预癫痫在大脑中的形成。这些问题的答案将意味着我们可以专注于制造针对癫痫过程的药物，改变疾病本身，而不仅仅是停止症状。我们的项目将帮助未来的患者，临床医生治疗癫痫，并为科学家提供新的知识，以进一步推动其他项目。