Can learning deficits in neurodevelopmental disorders be reversed by restoring gene function in the adult brain?

神经发育障碍中的学习缺陷可以通过恢复成人大脑中的基因功能来逆转吗？

• 批准号: MR/V013173/1
• 负责人: Karl Giese
• 金额: $ 50.3万
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FV013173%2F1
• 关键词: learning; deficits; neurodevelopmental; disorders; reversed

Approximately 1-2% of the UK population, 1.5 million individuals, suffer from intellectual disability, defined as a non-verbal IQ below 70. Almost half of these individuals also suffer from additional mental health problems. Intellectual disability severely affects the ability of individuals to function independently in society, placing a huge strain on families, carers and the healthcare system. We now know that 25% of intellectual disabilities have a genetic cause. It is widely assumed that the majority of these intellectual disabilities are caused by problems during brain development in the womb or shortly after birth and that these brain abnormalities are essentially irreversible. However, it remains possible that the genes responsible for the learning difficulties in these individuals have direct roles during learning and memory and that we may be able to correct, treat or ameliorate some of these learning difficulties, thereby significantly improving the quality of life for these individuals.The entrenched notion of the irreversibility of developmental brain disorders has been challenged by paradigm-shifting experiments in mice. Adrian Bird's group has shown that a severe, progressive developmental brain disorder that eventually result in death, Rett syndrome, can be reversed by restoring gene function in mice, even in adults already showing symptoms. These important findings raise the possibility that some of these disorders might be treatable by interventions after birth and even in adulthood. However, apart from Rett syndrome, we have little direct evidence that this is the case for other conditions. The focus of this pilot grant is to test this idea for a number of other genetic brain disorders associated with intellectual disability.We propose to determine if the genes associated with four different genetic conditions associated with intellectual disability have direct functions in learning and memory and if restoring normal gene function in mutant mouse models can reverse learning deficits. We will perform two different sets of experiments: 1) we will inactivate genes in brain cells (neurons) after they have formed in the developing brain, or in neurons in the adult brain, to determine if they function directly in learning and memory and 2) we will test if restoring gene function in neurons in adult mice with mutations in these genes can reverse deficits in learning and memory.This is a pilot project specifically focused on these two critical experiments. Brain development and disease is complex and many important questions remain to be answered. For instance, it will be of fundamental importance to eventually understand exactly how mutations in these genes cause intellectual disability in these patients. These genes most likely control many different processes, including those that operate during brain development and those responsible for the formation, storage and recall of memories. Rather than studying all these different processes, it is important that we first test if these genes function directly in learning and memory and if learning deficits are reversable. This measured approach will allow us to focus future efforts on the most relevant developmental time points, cell types and processes. If we find evidence that these genes function in adult neurons and that we can rescue learning deficits in adults, our future work will focus specifically on understanding how these genes function in adult neurons.

大约1-2%的英国人口，150万人患有智力残疾，智力残疾的定义是70以下的非语言智商。这些人中几乎有一半还患有额外的精神健康问题。智力残疾严重影响个人在社会中独立运作的能力，给家庭、照顾者和医疗保健系统带来巨大压力。我们现在知道，25%的智力残疾是由基因引起的。人们普遍认为，这些智力残疾中的大多数是由子宫中或出生后不久大脑发育过程中的问题引起的，这些大脑异常基本上是不可逆转的。然而，导致这些人学习困难的基因可能在学习和记忆过程中起到直接作用，我们或许能够纠正、治疗或改善其中一些学习困难，从而显著提高这些人的生活质量。在小鼠身上进行的范式转换实验，挑战了发育性大脑障碍不可逆转的根深蒂固的概念。禤浩焯·伯德的研究小组已经证明，一种严重的、进行性的大脑发育障碍，最终导致死亡，雷特综合征，可以通过恢复小鼠的基因功能来逆转，即使是已经出现症状的成年人。这些重要的发现提出了这样一种可能性，即这些障碍中的一些可能在出生后甚至在成年后可以通过干预来治疗。然而，除了Rett综合征，我们几乎没有直接证据表明其他情况也是如此。这项试点拨款的重点是测试这一想法是否与其他一些与智力障碍有关的遗传性大脑疾病有关。我们建议确定与四种与智力障碍相关的不同遗传疾病相关的基因是否在学习和记忆中具有直接功能，以及在突变小鼠模型中恢复正常的基因功能是否可以逆转学习障碍。我们将进行两组不同的实验：1)我们将在发育中的大脑形成脑细胞(神经元)或成年大脑神经元中的基因后使其失活，以确定它们是否直接在学习和记忆中发挥作用；2)我们将测试这些基因突变的成年小鼠神经元中恢复基因功能是否可以扭转学习和记忆障碍。这是一个专门针对这两个关键实验的试点项目。大脑发育和疾病是复杂的，许多重要的问题仍有待回答。例如，最终准确了解这些基因的突变是如何导致这些患者智力残疾的，这将是至关重要的。这些基因很可能控制着许多不同的过程，包括那些在大脑发育过程中运行的过程，以及那些负责形成、存储和回忆记忆的过程。与其研究所有这些不同的过程，重要的是我们首先测试这些基因是否直接在学习和记忆中发挥作用，以及学习缺陷是否可以逆转。这种有节制的方法将使我们能够将未来的努力集中在最相关的发育时间点、细胞类型和过程上。如果我们找到证据表明这些基因在成年神经元中发挥作用，并且我们可以挽救成年人的学习缺陷，我们未来的工作将专门专注于了解这些基因如何在成年神经元中发挥作用。