Dissecting the role interneuron dysfunction in Neurofibromatosis type I

点击翻译按钮获取中文摘要

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.