Dissecting the role interneuron dysfunction in Neurofibromatosis type I

剖析中间神经元功能障碍在 I 型神经纤维瘤病中的作用

• 批准号: 2899719
• 金额: --
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2899719
• 关键词: Dissecting; role; interneuron; dysfunction; Neurofibromatosis

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.

1型神经纤维瘤病（NF 1）是一种常见的遗传性神经系统疾病，影响约1：2700的个体1。大约50-60%的人会有某种形式的认知功能障碍。因此，作为一种具有高度认知功能障碍的单基因神经发育障碍，NF 1为理解发育过程中认知障碍的病因提供了宝贵的途径。这种认知功能障碍与发育中大脑中特定神经元群体（即interneurons）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起着至关重要的作用。已知中间神经元调节皮质回路内的信息流。因此，任何与它们的发育有关的扰动都会引起皮层处理和功能的损害。随着Patch-seq 3等最先进工具的出现，以下项目旨在利用同一细胞内的形态和生理信息补充单细胞转录组学方法。新出现的数据表明，在发育过程中的NF 1突变体4和成人大脑2中观察到抑制增加。这种抑制的增加反过来又与患者中通常观察到的认知功能障碍相关。然而，至关重要的是，我们不知道这种抑制的增加是如何在发育过程中发生的。我们假设NF 1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有影响。不适当的反应（例如增加抑制）反过来会导致信息流和处理的改变，并导致在NF 1突变体中观察到的认知功能障碍。为了测试这一点，我们将联合收割机结合黄的实验室在中间神经元发育方面的专业知识，贝儿的实验室在电生理学和计算建模方面的专业知识，以及Garg实验室在NF 1突变方面的专业知识。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NF 1突变如何导致认知功能障碍。我们预测，通过确定NF 1在调节中间神经元行为中的作用以及其在认知功能障碍中的作用，我们将能够开发新的治疗靶点，从而改善NF 1突变个体的生活质量。此外，曼彻斯特是国际公认的NF 1临床和研究工作中心，该博士项目将嵌入更广泛的NF 1转化研究计划。