Dissecting the role interneuron dysfunction in Neurofibromatosis type I

1型神经纤维瘤病(NF1)是一种常见的遗传性神经系统疾病，发病人数约为1：2700。这些人中大约有50%-60%会有某种形式的认知功能障碍。因此，作为一种具有高认知功能障碍外显率的单基因神经发育障碍，NF1为理解发育过程中认知障碍的病因提供了宝贵的途径。这种认知功能障碍被认为与发育中的大脑中特定数量的神经元，即神经元间的异常发育有关。虽然中间神经元只占大脑中所有神经元的20%，但它们在信息处理中发挥着至关重要的作用。众所周知，中间神经元调节大脑皮层回路内的信息流。因此，任何与其发育有关的干扰都会导致皮质处理和功能的损害。随着Patch-seq3等先进工具的出现，以下项目旨在用同一细胞内的形态和生理信息来补充单细胞转录方法。新出现的数据表明，在NF1突变体的发育过程中观察到了增加的抑制作用4，在成年大脑2中也观察到了这种抑制。这种抑制的增加反过来又与患者通常观察到的认知功能障碍有关。然而，关键的是，我们不知道这种抑制作用的增加是如何发生在发育过程中的。我们假设NF1基因突变对中间神经元如何能够检测、解释和反应局部网络活动的变化产生影响。不适当的反应(例如，增加的抑制)反过来会导致信息流和处理的改变，并导致在NF1突变体中观察到的认知功能障碍。为了测试这一点，我们将结合Wong实验室关于神经元间发育的专业知识，Belle实验室关于电生理学和计算建模的专业知识，以及Garg实验室关于NF1突变的专业知识。我们将使用成像质量细胞术、Patch-seq、病毒转导和行为等技术来了解中间神经元中的NF1突变如何导致认知功能障碍。我们预测，通过确定NF1在调节神经元间行为方面的作用，从而确定它在认知功能障碍中的作用，我们将能够开发新的治疗靶点，能够改善NF1突变个体的生活质量。此外，曼彻斯特在NF1的临床和研究工作是国际公认的中心，这个博士项目将被纳入更广泛的NF1翻译研究计划。

Neurofibromatosis type 1 (NF1) is a commonly inherited neurological disease that affects around 1:2700 individuals1. Around 50-60% of these individuals will have some form of cognitive dysfunction. Consequently, as a monogenic neurodevelopmental disorder with high cognitive dysfunction penetrance, NF1 presents an invaluable avenue in understanding the aetiology of cognitive impairments during development. This cognitive dysfunction has been linked to the aberrant development of a specific population of neurons in the developing brain, namely interneurons2. Although interneurons constitute only 20% of all neurons in the brain, they play a vital role in information processing. Interneurons are known to modulate the flow of information within cortical circuits. Consequently, any perturbations relating to their development induces impairments in cortical processing and function. With the advent of state-of the art-tools such as Patch-seq3, the following project aims to complement single-cell transcriptomic approaches with morphological and physiological information within the same cell. Emerging data has shown that increase inhibition have been observed in NF1 mutants during development4 and in the adult brain2. This increase in inhibition has in turn been associated with the cognitive dysfunction typically observed in patients. Critically however, we do not know how this increase in inhibition occurs during development. We hypothesise that the NF1 gene mutation has an impact on how interneurons are able to detect, interpret and react to changes in local network activity. The inappropriate reaction (e.g increased inhibition) in turn causes alteration in information flow and processing and contribute to the cognitive dysfunction observed in NF1 mutants.To test this, we will combine the expertise of the Wong's lab on interneuron development, the Belle's lab on electrophysiology and computation modelling, and the Garg lab on NF1 mutation. We will use techniques such as imaging mass cytometry, Patch-seq, viral transduction, and behaviour to understand how NF1 mutation in interneurons can lead to cognitive dysfunction. We predict that by identifying the role that NF1 in regulating interneuron behaviour and consequently its role in cognitive dysfunction, we will be able to develop new therapeutic targets that can improve the quality of life of individuals with NF1 mutations. Furthermore, Manchester is an internationally recognised centre for its clinical and research work in NF1 and this doctoral project will be embedded within the wider NF1 translational research programme.