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

大约1-2%的英国人口，150万人，患有智力残疾，定义为非语言智商低于70。这些人中几乎有一半还患有其他心理健康问题。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，大多数智力残疾是由子宫内或出生后不久的大脑发育问题造成的，这些大脑异常基本上是不可逆转的。然而，它仍然是可能的，在这些人的学习困难的基因有直接的作用，在学习和记忆过程中，我们可能能够纠正，治疗或改善这些学习困难，从而显着提高生活质量的这些individuals.The根深蒂固的观念，发育性脑障碍的不可逆性已受到挑战的范式转移实验小鼠。Adrian Bird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，Rett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，即这些疾病中的一些可能是可以通过出生后甚至成年后的干预措施来治疗的。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与智力残疾的其他遗传性脑疾病的数量。我们建议确定与智力残疾相关的四种不同遗传条件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基因功能是否可以逆转学习缺陷。我们将进行两组不同的实验：1）我们将在发育中的大脑中形成脑细胞（神经元）后，或在成年大脑的神经元中，以确定它们是否直接在学习和记忆中起作用; 2）我们将测试在这些基因突变的成年小鼠中恢复神经元中的基因功能是否可以逆转学习和记忆的缺陷。这是一个试点项目。特别关注这两个关键实验。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如何导致这些患者的智力残疾将具有根本的重要性。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起作用的过程，以及那些负责记忆形成、储存和回忆的过程。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起作用，以及学习缺陷是否是可逆的。这种测量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。如果我们发现这些基因在成年神经元中发挥作用的证据，并且我们可以挽救成年人的学习缺陷，我们未来的工作将特别关注这些基因在成年神经元中的功能。

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.