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

大约有1-2%的英国人，即150万人患有智力障碍，即非语言智商低于70。这些人中几乎有一半还患有额外的心理健康问题。智力残疾严重影响个人在社会中独立运作的能力，给家庭、护理人员和医疗保健系统带来巨大压力。我们现在知道25%的智力残疾与遗传有关。人们普遍认为，这些智力障碍大多是由子宫内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，仍然有可能导致这些人学习困难的基因在学习和记忆过程中起着直接的作用，我们可能能够纠正、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。发育性脑障碍的不可逆性这一根深蒂固的观念已经被在老鼠身上进行的范式转换实验所挑战。艾德里安·伯德（Adrian Bird）的研究小组已经证明，一种最终导致死亡的严重进行性大脑发育障碍——雷特综合征（Rett syndrome），可以通过恢复老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一种可能性，即这些疾病中的一些可以在出生后甚至成年后通过干预来治疗。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在与智力残疾相关的许多其他遗传性脑部疾病中测试这一想法。我们打算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的脑细胞（神经元）或成年大脑中的神经元中灭活基因，以确定它们是否直接在学习和记忆中起作用；2)我们将测试恢复这些基因突变的成年小鼠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，最终确切地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作的基因，以及那些负责记忆形成、存储和回忆的基因。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，以及学习缺陷是否可以逆转。这种可测量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。如果我们发现这些基因在成人神经元中起作用的证据，我们就可以挽救成人的学习缺陷，我们未来的工作将集中在理解这些基因在成人神经元中的作用。

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.