Dr Asami Oguro-Ando, The Institute of Biomedical and Clinical Science, College of Medicine and Health, University of Exeter
Dr Paul Chadderton, School of Physiology, Pharmacology & Neuroscience, University of Bristol
Prof Jonathan Mill, College of Medicine and Health, University of Exeter
Abnormality of social interaction and motor coordination are the common symptoms of autism. Current data indicate that disruption to the JAKMIP1 gene results in autism phenotypes in mice. This project will focus on investigating disrupted neural processing in the cortex and cerebellum using integrated bioinformatics, molecular biology, and electrophysiology.
This studentship aims to understand the influence of JAKMIP1 dysfunction on neural circuit activity in the cerebellar and cerebral cortices. Autism is a major mental health issue affecting 1 in 100 people in the UK, defined by three core features, primarily impaired social interactions, language impairment, and repetitive or restricted behaviours. Along with the cerebral cortex, the cerebellum, or ‘little brain’, is increasingly implicated in the expression of autism-like behaviours. Autism has a strong genetic component, but the mechanistic links between behavioural phenotypes and molecular- and brain circuit pathology are poorly understood. Recently, dysfunction of janus kinase and microtubule interacting protein 1 (JAKMIP1), a regulator of neuronal translation and glutamatergic signalling, has been shown to contribute to both inherited and idiopathic autism. The JAKMIP1 protein is involved in core autism behaviours including social defects (Berg et al., Neuron 2015). To understand the molecular functions of JAKMIP1, we have knocked out JAKMIP1 in human neuroblastoma cells using the novel genome-editing technique, CRISPR-Cas9 system. We will identify the specific cellular cascades targeted by JAKMIP1 and investigate their links with autism. We will then explore how JAKMIP1 deficiency induces social dysfunction and motor coordination through altered neural circuit activity in the brains of JAKMIP1-KO mice.
Experimental Design: This project will combine novel cutting-edge techniques including bioinformatics, genome-editing, molecular cellular biology, microscopy and in vivo electrophysiology to address the following specific aims: 1. Identify potential therapeutic targets for modifying autism-associated neuronal and brain morphological phenotypes by: a. RNA-sequence data analysis (bioinformatics and Crispr genome engineering): Identify cellular pathway candidates for pharmacological modulation using JAKMIP1-KO neuroblastoma cells. b. Molecular biological analysis (neuronal morphological analysis and target pathway analysis in vitro): Detect target pathways of JAKMIP1 by examining protein/mRNA levels using western blot and qPCR. c. Brain anatomical screening (Immunohistochemistry and confocal microscopy): Measure the effect of Jakmip1 loss on development in the cerebellum and cerebral cortex. 2. Characterise how JAKMIP1-deficiency alters information processing in neural circuits by: a. In vivo electrophysiological recording in Jakmip1-KO mice: Measure neuronal ensemble activity with NeuroPixels probes in the cerebellum and cerebral cortex of awake behaving animals. b. Functional neuronal connectivity in JAKMIP1 dysregulated brain: Assay strength and dynamics of synaptic connections using optogenetics in Jakmip1-KO mice.
The successful candidate will establish the influence of a key autism risk gene on neural processing, potentially leading to new breakthroughs in diagnosis and intervention.
To apply for this project, please complete the application form at https://cardiff.onlinesurveys.ac.uk/gw4-biomed-mrc-doctoral-training-partnership-student-appl
by 5pm Friday 25 November 2019.