Applications are invited for 3.5 year full-time fully funded PhD studentships spanning basic and translational brain sciences in the biological mechanisms underlying autism. These studentships represent an exceptional opportunity for well-qualified, motivated individuals to conduct new research in an expert and highly-supportive environment. The projects on offer are (alphabetical by 1st supervisor):
Candidates can select up to three of the PhD projects listed - each application should be submitted on a separate application form. In the application form you should indicate why you are interested in the project and why you would be a good fit for the project.
Applicants should have a good (2:1 or higher) undergraduate degree in a relevant subject (including, but not necessarily limited to, neuroscience, biomedical sciences, molecular biology, genetics, or computational biology).
The successful candidate will be based within SIDB in the College of Medicine and Veterinary Medicine (CMVM) at the University of Edinburgh. They will join a vibrant, successful, highly-collaborative community of researchers across the University of Edinburgh examining the biological mechanisms underlying autism.
This is a SIDB-funded award. It will provide an annual stipend for 3.5 years of £15,844 per annum which will be amended annually in line with annual RCUK stipend percentage changes (currently based on the GDP deflator), plus tuition fees (including international).
Applicants should also meet the entry requirements – including English language requirements – for admission to postgraduate programmes at the University of Edinburgh.
Shortlisted candidates will be asked to make contact with the named supervisor(s) for their chosen project(s) to discuss the project in more detail; in most cases this will take the form of meetings in-person on or near the interview day, but discussions can take place by phone or Skype if necessary. The studentships will begin in September 2022.
If you have an enquiry about the programme please email Jane Wright (SIDB Scientific Administrator).
Understanding how neurodevelopmental disorder-causing missense mutations in EEF1A2 impact on neuronal protein synthesis
De novo mutations in the eukaryotic elongation factor EEF1A2 have been reported in over 100 individuals with epilepsy, intellectual disability and autism. This translation factor is specific for the brain and muscle, and to date over 40 different missense mutations have been recorded in patients, with a range of severity.
Our project aims to investigate the effects of eEF1A2 mutations on protein synthesis, assessing translational fidelity and efficiency and looking for any impact on the neuronal proteome. With so many mutations, an interference in eEF1A2's capacity for protein synthesis seems likely, and there is evidence to suggest that slight perturbations in proteostasis can have severe consequences in long-lived, terminally differentiated neuronal cells.
Indeed, many neurodevelopmental disorders converge at the point of protein synthesis, and there is increasing evidence that aberrant proteostasis is a key underlying cause of neurodegeneration. We aim to elucidate the mechanism by which the eEF1A2 mutations affect development, providing insight into the many disorders underpinned by defects in neuronal protein synthesis.
Visuomotor Processing in Autism Spectrum Disorders: A Decision-Making Perspective
Disrupted sensorimotor processing is a cornerstone characteristic in a range of Autism Spectrum Disorders. However, defects in the neural and computational mechanisms underpinning the decision-making associated with sensorimotor control remain poorly explored and poorly understood. Understanding such cognitive processing requires not only a description of neural activity during cognitive performance but also an understanding of the nature of the processing task itself. Our research project aims to combine widefield cortical imaging with psychophysical modelling of decision-making as a drift diffusion process to generate a mechanistic understanding of sensorimotor decision making during a touchscreen-based visual discrimination reaching task. A central question of this project relates to the recovery of the cognitive processes in rescue studies. For example, it has been established that a reintroduction of the MECP2 protein in rodent models of Rett’s Syndrome rescues the lethal phenotype of the MECP2 knock-out. However, the extend of recovery in the cognitive processes of these mice remains poorly explored. This is an important question with wide implications both in the study of neural circuits as well as for potential therapeutic intervention in patients with neurodevelopmental disorders; can one ever fully recover from such a disorder?
Designing and Testing Molecular Therapies for SynGAP1 Deficiency
In 2009 Hamdan et al. identified novel de novo mutations in SynGAP1 (Synaptic Ras-GTPase Activating Protein1) gene (MIM #603384), with autosomal dominant inheritance, in patients with NSID (Non-Syndromic Intellectual Disability). Lately, SynGAP1 mutations have bene associated also to SID, autism spectrum disorders and epilepsy. An increasing number of patients carrying SynGAP1 mutations have been reported suggesting that it might be a frequent cause of NSID. ID, with 1 to 3% of affected individuals over the total population, is the most frequent disorder diagnosed in children. Patients present consistent limitations in cognitive abilities and adaptive behaviour.
SynGAP1 is a component of the postsynaptic density protein complex and it is involved in AMPAR trafficking regulation and modulation of synaptic plasticity and morphology. We hypothesize that the reestablishment of protein normal levels would avoid the insurgence of intellectual and behavioural abnormalities. My thesis project aims to design and test molecular therapies for SynGAP1-deficiency in rodent models of SynGAP1 deficiency. Specific aims include:
· To investigate expression pattern of SynGAP1 isoforms during development.
· To design and optimize a robust behavioural phenotyping battery.
· To design and generate rational gene therapy cassettes for testing efficacy and safety in rodent models of Syngap1 deficiency.
What drives NMDA receptor dependent metaplasticity and how is it altered in monogenic models of ASD?
Autism spectrum disorder (ASD) is a complex polygenic disorder that can affect up to 1 in 160 children. Mutations in the N-methyl-D-aspartate receptor (NMDAR), one of the major excitatory ion channels in neurons, have been implicated in ASD. NMDARs are highly complex and can be composed of GluN1 and GluN2 subunits (GluN2A-D). In the visual cortex, there is a developmental upregulation of GluN2A but interestingly this can be halted in the juvenile stage, where GluN2B dominates, by sensory deprivation. As sensory deprivation affects electrical activity of neurons, the ratio of GluN2A:GluN2B is thought to be tightly controlled by sensory integration. ASD has been associated with impaired sensory integration, therefore, posing a major challenge for children with ASD. Using novel knock-in mouse models, this project aims to determine how sensory input differentially influences the levels of GluN2A and GluN2B at the synapse in vivo, with particular focus on the their distinctive C-terminal domain sequences and their role in activity-dependent synaptic changes.
Investigating the role of rough-and-tumble play in the development of socio-emotional phenotype in rat models of autism spectrum disorder
Play is a critical and ethologically relevant aspect of the developmental process across phyla and has been particularly well characterised in laboratory rats. Evidence from play deprivation studies strongly suggests that playful interaction during the juvenile period is necessary for normal socio-emotional development and contributes to a stress resilient phenotype in adulthood. Autism spectrum disorder (ASD) is characterised in part by difficulties with reciprocal social interaction and often comorbid with anxiety and depression. Because of its relevance to development in both humans and rats, and the relative ease with which play can be observed in rats in the laboratory, juvenile play is a fruitful behaviour to study in relation to ASD. However, separating the effects of play versus non-playful social behaviour on development is difficult. Most research on play has relied on social isolation to restrict play, although general social interaction and play may contribute differently to development. To address this issue, a novel housing system will be developed to manipulate access to play during specific periods of juvenile development while still allowing direct interaction with peers.
Convergence of spatial representation deficits in autism spectrum disorders
Autism spectrum disorders involve impairments to episodic memory, episodic future thinking, and navigation. The causal mechanisms underlying these deficits, which rely on the ability to generate and maintain representations of space, are unknown. This project will test the hypothesis that deficits in spatial codes in the medial entorhinal cortex (MEC) are a common predictor of phenotypic deficits in ASD models.
Cells in the MEC provide a rich representational repertoire to support complex navigational and spatial processes through the encoding of multiple spatial variables. Lesion or cell type specific manipulations of this region cause spatial memory and navigation impairments. To test whether encoding within the MEC is impaired in ASD models, experiments will employ tetrode recordings of populations of neurons in the MEC of awake, freely moving ASD mice and in mice performing virtual reality-based tasks that specifically probe MEC-dependent path integration.
Developing molecular and genetic therapies for Fragile X Syndrome
Fragile X Syndrome (FXS), is the most common form of inherited intellectual disability and the leading single gene cause of autism. The disorder manifests as a neurodevelopmental disorder, afflicting around 1 in 4000 males and 1 in 8000 females. There is currently no cure. FXS is caused by epigenetic silencing of the X-linked FMR1 gene that encodes the Fragile X Mental Retardation Protein (FMRP). This dynamic protein is involved in multiple processes, primarily through its inhibitory effect on protein translation of target mRNAs by stalling ribosomal subunits.
FXS is a monogenic disorder, making it a potential candidate for a gene therapy approach to treatment. Delivering a functioning copy of the FMR1 gene back to patients could represent a transformative therapy for FXS. We will test this feasibility of this approach by delivering functioning copies of FMR1 to a mouse model of FXS, using a virus delivery system. We will assess if re-expression of FMRP is able to prevent the development of FXS-associated phenotypes in the FXS rodent models, giving us key insights into the possibility of this approach being developed for patients.
Elucidating the developmental trajectory of the dysfunctional synaptic vesicle (SV) recycling at the presynapse in autism spectrum disorder (ASD) models
Dysfunctional SV recycling was seen in multiple ASD models but it is not known whether this phenotype is transient or permanent. The time-course analysis of SV recycling will give us insights wherein the timepoint for pharmaceutical intervention for treating ASD in the future.
Identifying the role of microglia in the developing brain and in plasticity
Microglia are the immune cells of the CNS and play an important role in synaptic maturation and plasticity. During neurodevelopment a large number of synapses are engulfed by microglia and are eliminated in a process termed synaptic pruning. The remaining synapses are strengthened, forming mature neuronal circuits. Studies have shown that disrupted microglial function results in altered synaptic development, and this may contribute to deficits in cognition and behaviour associated with autism spectrum disorders (ASDs). This project will use the newly generated Csf1r∆FIRE/∆FIRE mouse model which selectively lacks brain microglia to investigate the effects of microglia depletion on synaptic development and plasticity. Quantification of structural properties such as synaptic density, dendritic morphology and spine density will be carried out. Synaptic activity will also be measured to investigate the effect of microglia on synaptic plasticity. Lastly changes in behaviour typical of ASD will be assessed.
Circuit deficits associated with SynGAP1 haploinsufficiency
Syngap haploinsufficiency is a relatively common cause of intellectual disability, around 1% of ID cases are caused by this mutation. Most of the patients suffer from epilepsy as well, and in half of the cases it deals with autism spectrum disorders. Patients show delayed development of motor skills, hyperactivity and impairments in social and cognitive abilities.
This disease is caused by an autosomal dominant mutation in the SynGAP1 gene. SynGAP1 is a constituent of the post synaptic density protein complex and contributes to regulate excitatory synapse plasticity. However, how this mutation alters brain connectivity and this eventually leads to ASD/ID remains unknown. To address this issue, we are going to work on a synGAP1-deficiency rat model. We aim to both record and manipulate specific brain regions with in vivo electrophysiology and virus-guided optogenetics, respectively, during social behaviour tasks to detect which are the main impaired circuits under Syngap social impairments.
Investigating the development of functional thalamocortical circuitry in a rat model of Fragile X Syndrome
Fragile X syndrome (FXS) is the most common monogenic cause of autism. It is caused by silencing the Fmr1 gene and it is commonly investigated in rodents with a deletion of this gene (Fmr1-KO), which recapitulate many of the behavioral phenotypes of FXS. Previous experiments have shown synaptic alterations in thalamocortical connections during early development in the Fmr1-KO mouse. The head direction signal is generated in the brainstem and is relayed to the postsubiculum, in the cortex, through the anterodorsal thalamic nucleus (ADN), an example of thalamocortical projections. To examine the functional effects of altered thalamocortical connectivity, this project will investigate the function of the head direction circuitry in young (P8-P14) Fmr1-KO rats. I will use silicon probes to record neuronal activity in the postsubiculum and ADN acutely under anaesthesia and/or during awake experiments, in order to examine the development of direction coding and temporal co-activity relationships in this circuit, in collaboration with researchers at McGill University.
Developing a meta-research framework for experimental models of ASD
Meta-research techniques are increasingly used to summarise research literatures, and inform areas of research improvement, such as the improved translation of findings from the lab to the clinic.
Systematic review is a structured meta-research approach that follows a pre-specified protocol to identify and assess evidence related to a specific research question. Meta-analyses combine quantitative outcome data from individual studies to identify average effects and effect moderators (including aspects of study design).
Preclinical meta-research efforts have led to substantial improvements in study design and reporting in other areas of neuroscience research. However, laboratory autism spectrum disorder (ASD) research has not yet benefited from systematic evaluation.
This project aims to build an infrastructure to systematically identify all published laboratory ASD research and to assess its experimental validity.
Neural Mechanisms of Kinship Behaviour
Attachment is a biologically driven construct that exists between an infant and their primary caregiver. Hypothesized to preserve the species through nurturing behaviours, attachment between an infant and their caregiver has been shown to have strong influences on the infant's cognitive and socio-emotional development, as well as their relationships (familial, social, and romantic) later in life.
Under the broader research of the kinship lab, my project seeks to understand the neural circuits that underly natural attachment behaviours between infants and their caregivers. Via a combination of in vitro and in vivo electrophysiology, imaging, circuit mapping, and behavioural analyses, we are hoping to understand how and when the neural signatures of kin relationships arise during development, how endogenous opioids influence attachment, and how this circuit is represented neurally in the brain. After laying this foundation in the neurotypical brain, we hope to apply this research to common models of autism spectrum disorders (ASD) and other neurodevelopmental disorders (NDD) to understand where this circuit deviates between neurotypical and neurodivergent methods of attachment.
Translation profiling of epileptogenesis in neurodevelopmental disorders
Pediatric epilepsy is a feature of several neurodevelopmental disorders, including Fragile X Syndrome. The ethology of seizures in these disorders is poorly understood. However, treatments that normalize protein synthesis have been shown to prevent the emergence of pathological changes in Fmr1-/y mouse models, including epileptiform activity and susceptibility to audiogenic seizures (AGS).This suggests mRNA translation is required for the generation of epilepsy (epileptogenesis) in this model.
My research project is focused on identifying the mistranslating mRNAs that contribute to epileptogenesis. In particular, to elucidate the critical neuron populations contributing to AGS in Fmr1-/y and assess the changes in mRNA translation that occur within seizure-generating neurons. To do so, I am using different molecular biology and imaging techniques, cell type-specific Translating Ribosome Affinity Purification (TRAP) and whole brain imaging.
Identifying convergent dysregulation of mRNA translation in multiple models of autism
Intellectual disability and autism spectrum disorders have been increasingly diagnosed in the population and the developmental, cognitive and behavioural challenges create a significant burden for affected individuals and families. Focus on Fragile X, an identified single-gene cause of ASD/ID, resulted in the identification of dysregulated mechanisms underlying the disease. Upon transcriptional silencing of FMR1 gene, the loss of encoded protein FMRP results in inhibition of local translation at synapses leading to excessive synaptic protein synthesis. A similar dysregulation of protein synthesis is seen in other ASD/ID models including Syngap+/- model of SYNGAP1 haploinsufficiency syndrome. This strengthen the hypothesis that aberrant synaptic mRNA translation could be a point of convergence for multiple genetic causes of ASD/ID.
In this direction we aim to:
Convergent molecular mechanisms of Autism Spectrum Disorder resulting from mis-processing of RNA-binding proteins
This PhD project investigates the mis-processing of RBPs in the driving of ASD disease progression. Specifically, it will test the hypothesis that microexon skipping in these RBP transcripts initiates changes to their protein regulatory activities that are detrimental to neurodevelopment and contribute to the convergent transcriptome-wide signatures found in genetically different cases of autism. For this purpose, brain organoids are generated to model these microexons skipping in selected RBPs of interest using CRISPR-Cas9 and iPSCs technologies and characterized by multi-omic approaches such as iCLIP.