Development of a new model system for studying animal models of intellectual disability and autism spectrum disorders

The Institute of Medical Sciences (IMS), University of Aberdeen, is recruiting a cohort of 7 PhD students across its broad themes in neuroscience, immunology, microbiology, molecular biology and computational biology. The studentships are linked to 7 new academic appointments in the Institute. Applications are invited for 4-year fully funded PhD studentships commencing 1st October 2023. The application deadline is 6th February 2023.

Project Description

Intellectual disabilities (IDs) and autism spectrum disorders (ASDs) are heritable neurodevelopmental conditions, yet a wide range of different genes are associated with them. It has been hypothesised that this large number of ID/ASD genes ‘converge’ onto a much smaller number of molecular pathways and neuronal pathologies. ID/ASD-related genes can be broadly grouped into those associated with synapse development and maintenance, and those involved in transcription and/or chromatin remodelling ^1,2. However, there is currently little direct evidence for the convergence of phenotypes within these broad categories, making the development of new therapeutics particularly challenging. Testing for convergent phenotypes in different monogenic models of ID/ASD has been difficult, due to the complex interplay between different types of neurons, and issues with differentiating direct effects of genes from homeostatic compensation.

The aim of the project is to develop a new model system to study ID/ASDs, using neurons of the inferior olive (IO). IO neurons express the majority of ID/ASD genes, are a 99.9% homogenous population, have elaborate dendritic spines³, and easily quantifiable postsynaptic responses to afferent input ^4,5. Importantly complexities such as local feedback mechanisms, which in other brain areas may confound the evaluation of convergent mechanisms, are absent from the IO. In pilot experiments, we have shown that IO neurons display convergent phenotypes linked to an increase in excitability, across three ID/ASD models: Fmr1^-/y, Syngap1^+/- and Nlgn3^-/y.

We will aim to elucidate the mechanisms underlying convergent ID/ASD phenotypes in IO, with the objective of subsequently reversing the changes observed in ID/ASD models. To address this, we will combine optogenetic approaches and advanced imaging methods to:

1. Determine whether the increase in excitability in IO across ID/ASD models is due to a change in ion channels or signalling pathways.
2. Determine if the increase in excitability is linked to structural [BG1] changes at the level of dendritic spines.
3. Determine the molecular mechanisms underlying the changes observed. 4) Determine whether ID/ASD phenotypes in IO can be reversed using pharmacological or gene therapy approaches.

Through these objectives, we will determine whether there are convergent phenotypes [BG2] across ID/ASD models and whether these phenotypes can be reversed. This will increase our understanding of how ID/ASD-related genes regulate neuronal function and potentially allow for the development of interventions and treatments for ID/ASD patients.

By the end of the project, the student will have expertise in neural circuit manipulation using optogenetics (and associated surgical techniques), electrophysiological recordings from ex-vivo slice preparations, super-resolution confocal microscopy, electron microscopy, as well as computational analysis of morphological and physiological data.

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Candidate Background

Applicants should hold a minimum of a 2:1 UK Honours degree (or international equivalent) in a relevant subject (including, but not necessarily limited to, neuroscience, biomedical sciences, molecular biology, genetics, or computational biology). Those with a 2:2 UK Honours degree (or international equivalent) may be considered, provided they have (or are expected to achieve) a Distinction or Commendation at master’s level.

We encourage applications from all backgrounds and communities, and are committed to having a diverse, inclusive team. Informal enquiries are encouraged. Please contact Dr Derek Garden ([Email Address Removed]) for further information.

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APPLICATION PROCEDURE:

• Formal applications can be completed online: https://www.abdn.ac.uk/pgap/login.php
• You should apply for Medical Sciences (PhD) to ensure your application is passed to the correct team for processing.
• Please clearly note the name of the supervisor and exact project title on the application form. If you do not mention the project title and the supervisor on your application, it will not be considered for the studentship.
• Your application must include: A personal statement, an up-to-date copy of your academic CV, and clear copies of your educational certificates and transcripts.
• Please note: you DO NOT need to provide a research proposal with this application
• General application enquiries can be made to [Email Address Removed]
• Interviews will be held on 23rd and 28th February 2023.