SIDB awards internal grants for new collaborative projects in autism research. This is an annual grant call which supports novel basic science and clinical developments in areas covered by SIDB's scientific aims. A key aim of the award programme is to enable SIDB members to complete novel interdisciplinary work across the SIDB research groups.
Click the years below to see what projects have been funded to date.
'In cage monitoring for endophenotypes of neurodevelopmental disorders, and elucidating the role of eEF1A isoforms at the synapse' (Cathy Abbott)
Research question: Do mouse models of NDD typically show alterations in sleep/wake cycles? Can we use in cage monitoring to assess aspects of reversal? Do mutations in eEF1A2 cause autism by impacting on the role of eEF1A1 in synapse elimination?
'Establishing the functional consequences of translation elongation factor isoform switching during neurodevelopment' (Cathy Abbott)
Research question: Are the near-identical eEF1A isoforms, expressed at different stages of neurodevelopment, functionally equivalent? If not, what is the effect does enforced expression of eEF1A1 on neuronal function, is it neuroprotective? If so, could intervention in the switching process ameliorate neurodevelopmental phenotypes?
'Generating a pipeline for the rapid testing and optimization of gene therapy cassettes for neurodevelopmental disorders' (Stuart Cobb)
Research question: Rett syndrome (RTT) is a neurodevelopmental disorder resulting from loss-of-function mutations in the MECP2 gene. Using mice that accurately model RTT, we previously showed that restoring MeCP2 reverses RTT-like phenotypes. Here we seek to translate these findings by systematically testing multiple alternative gene therapy cassette designs. This pipeline will establish a test-bed applicable to other ASDs. To achieve this we will extend this approach in year two to a second ASD – Syngap1 deficiency.
'Dysfunctional activity-dependent bulk endocytosis in fragile X-syndrome and autism' (Mike Cousin)
Research question: Activity-dependent bulk endocytosis (ADBE) is triggered specifically during intense neuronal acitivty. Its dysfunction should therefore disproportionately impact on neurons/circuits that utilize these physiological firing patterns. We have identified an ADBE defect in FMR1 knockout neurons, suggesting this may contribute towards the synaptic/circuit defects in fragile X syndrome. Our research questions are: 1) What is the mechanism of FMRP in ADBE?, 2) Is ADBE dysfunction conserved in autism?, 3) Is ADBE a viable target for therapy?
'In-cage lifetime monitoring of rodent behaviour' (Ian Duguid)
Research question: Autism is charaterised by complex, multi-faceted behavioural phenotypes that include altered sensory motor processing and intellectual disability. Elucidating robust behavioural correlates in animal models has been challenging and difficult to repeat across laboratories. This proposal seeks pilot funding to establish home-cage monitoring as an unbiased approach to exploring animal behaviour. This system will allow effective and efficient cross model comparisons to examine behavioural convergence across a range of models.
'Identifying convergence in chromatin disorders: Whole genome sequencing of ‘mutation-negative’ individuals with Cornelia de Lange Syndrome' (David Fitzpatrick)
Research question: Whole genome sequencing will be used to identify novel causative genes in 100 “mutation-negative” affected individuals from the MRC HGU Cornelia de Lange Syndrome (CdLS) cohort. Our group and others have shown that CdLS can be caused by mutations in both cohesin-related CdLS genes (NIPBL, SMC1A, SMC3, RAD21, HDAC8) and core SFARI genes (SETD5, ANKRD11, KMT2A). Knowledge of all CdLS causative loci will help identify common biological mechanisms and inform strategies for therapies.
'Comprehensive in vitro modelling of Cornelia de Lange syndrome (CdLS) in human differentiated dopaminergic neurons to identify convergent cellular pathology with translational potential for non-syndromic autism' (David Fitzpatrick)
Research question: CdLS in a severe, multisystem neurodevelopmental disorder. Initially all causative genes encoded components of the cohesin system. Subsequently mutations were identified in genes encoding chromatin associated proteins with no known link to cohesion. The mechanism of neuronal disfunction in CdLS is currently unknown. We propose a screen of all CdLS-associated genetic perturbations modeled in human-derived differentiated neurons; identifying common defects in cellular/sucellular morphology, transcriptome and proteome likely to help future translational research.
'Social behaviour in ASD rodent models; from genes to circuits to therapeutics' (Christos Gkogkas)
Research question: Changes in social behaviour are a salient feature of ASDs. We recently described a new social ethologically relevant paradigm in mice based on social preference for familiars over strangers. We will implement this and other assays in monogenic rat models of ASD selected by the core SIDB group, aiming to identify converging pathways of social behaviour dysfunction during critical periods of postnatal development. Subsequently, we will identify the molecules, cells and circuits underlying social behaviour, as a basis for designing novel therapeutics.
'Single synapse resolution molecular mapping of developmental trajectories across the whole mouse brain in monogenic models of autism' (Seth Grant)
Research question: Is there a convergence in the developmental trajectories in the synaptic organization of the brain in monogenetic disorders of ASD?
'Prototyping 3E: Developing and Evaluating a System for Efficient Environmental Enrichment' (Oliver Hardt)
Research question: The everyday life of laboratory rats is extraordinarily dull and, compared to their wild counterparts, they live in a state of perpetual deprivation. We therefore predict that standard housing conditions affect the developmental trajectories and cognitive-behavioural status of laboratory rats. This pilot project will establish a low-cost, highly efficient environmental enrichment system to test whether providing stimulating species-appropriate housing for groups of up to 20 animals will result in novel behavioural phenotypes for characterising and assessing ASD in rats.
'Investigation of a therapeutic strategy direction for the treatment of Autism and Intellectual Disability caused by SynGAP1 Haploinsufficiency' (Noboru Komiyama)
Research question: Our overarching question is whether the phenotypes caused by SynGAP1 haploinsufficiency, which is associated with human Intellectual Disability and Autism Spectrum Disorders, are due to a reduction in the enzymatic activity of SynGAP1 or mediated through alteration of other functions of the molecule, such as its structural and scaffolding roles. Answering this question is crucial for the future direction of research towards development of therapeutic strategies.
'Creation of a technical support facility for electrophysiology (systems) and behavior labs' (Richard Morris)
Research question: The primary research issue is to ensure that the various constituent laboratories of the systems and behavior sub-groups of SIDB can readily create new apparatus quickly to address novel issues; can develop monitoring and analysis software; can get advice on recently purchased equipment in these domains; can get help with setting up equipment, maintenance and repair.
'Understanding role of the ubiquitin proteasome system in ASD/ID' (Emily Osterweil)
Research question: This proposal will test the hypothesis that aberrant UPS function is a point of convergence for multiple genetic causes of ASD/ID that can be targeted to correct neurological phenotypes.
'Using animal transgenic and human stem cell technologies to model genetic mutations associated with autism' (David Price)
Research question: Development and validation of stem cell-based methods to unravel the molecular and cellular actions of autism-related genes during forebrain development.
'Mismatch between visual flow predictions and visual inputs in the mouse visual cortex: A test for predictive coding impairment in mouse models of autistic spectrum disorders' (Nathalie Rochefort)
Research question: Theoretical studies suggest that many autism’s salient phenotypes may be manifestations of impairments in predictive abilities. Recent studies in the mouse primary visual cortex (V1) have shown that top-down projections from A24b/M2 to V1 carry a prediction of visual input based on the motor output of the mouse. The aim of this project is to use the same experimental paradigm to test whether visual flow predictions are disrupted in mouse models of autistic spectrum disorders.
'Integrating genetic, phenotypic and clinical data to improve our understanding of autism' (Ian Simpson)
Research question: Can joint analysis of genotype, phenotype and clinical data produce new insight into autism aetiology not discernible from analysing these data in isolation? Can analysis at the patient level improve our understanding of the co-occurrence and penetrance of autism features? Can the inclusion of clinical, behavioural, developmental milestone, growth, age and gender data lead to new outcome measures for clinical trials? Can these integrated data and analysis methods be of diagnostic and predictive value?
'Neurocognitive phenotypes in monogenic developmental disorders' (Andrew Stanfield)
Research question: Is there convergence in the human phenotypes (clinical, neuropsychological and electrophysiological) of fragile X syndrome and SYNGAP1 associated intellectual disability?
'Evaluation of hippocampal population codes in Fragile X models' (Gulsen Surmeli)
Research question: How does deletion of the gene encoding FMRP affect hippocampal spatial codes? We propose to evaluate specific hypotheses motivated by cellular and behavioural deficits previously reported for FMRP mutant animals. We will directly address codes for place, context, time (days) and objects.
'To establish a wireless, high-density EEG recording system to monitor brain rhythms chronically in rodent models of autism' (Emma Wood)
Research question: Brain rhythms are altered in many forms of ASD with disturbances in sleep rhythms and epilepsy as hallmark features. This project seeks to establish a chronic, high-density electrode, EEG recording system to study brain rhythms in rat models of autism. The initial studies will provide a proof-of-principle for future applications to a range of monogenic ASD models. This collaborative grouping will test the hypothesis that: EEG disturbances characterized by altered sleep and epilepsy converge across monogenic forms of autism.
'Juvenile development of interactions between hippocampus and medial prefrontal cortex in a rat model of Fragile X Syndrome (FXS)' (Antonis Asiminas)
Research question: What is the developmental trajectory of interactions between hippocampus(HPC) and medial prefrontal cortex(mPFC) and how is it affected by the loss of FMRP. We propose to explore these interactions at a single neuron level, at a neuronal ensemble level (looking at temporal coordination patterns) and at a local field potential (LFP) level (looking at oscillatory synchrony between the brain regions of interest).'
Is NMDA receptor dependent metaplasticity altered in two monogenic models of ASD?' (Giles Hardingham)
Research question: NMDA receptors also play a crucial role in activity-dependent brain development including dynamically regulating the threshold of neuronal activity that toggles between the induction of synaptic weakening and synaptic strengthening (i.e. metaplasticity). Furthermore, mutations in components of the NMDA receptor complex have been causally-linked to autism. The experiments outlined in this proposal will directly examine whether NMDA receptor mediated metaplaticity in the developing cortex is a convergent pathophysiology in two models of ASD.
'Calcium imaging in prefrontal cortex during social interactions between freely-moving Fragile-X rats' (Richard Morris)
Research question: Work by Zhou et al, Science (2017) using mice has raised the suggestion that plasticity on a thalamic to prefrontal cortex pathway may mediate this experiental component. We now seek to explore this possibility further using genetically encoded calcium indicators in freely-moving rats, and believe this relevant to autism research as a window into the neural mechanisms of social withdrawal.
'Spatial representation and scene construction in mouse models of autism spectrum disorders' (Matt Nolan)
Research question: Scene construction has been proposed as a key component of cognitive processes such as episodic memory and episodic future thinking that are impaired in autism spectrum disorders (ASDs). We propose initial tests of the hypothesis that deficits related to scene construction in ASD models are due to failed computations within the medial entorhinal cortex (MEC). In this case we expect to find deficits in neural coding within the MEC and in behaviours requiring the MEC.
'Dendritic spines in the inferior olive as an assay for mechanistic convergence between genetic models of autism' (Matt Nolan)
Research question: How can we most productively investigate synaptic functions of autism-related genes? Many genes associated with autisms are enriched in the inferior olive (IO) and neurons in the IO are distinguished by elaborate dendritic spines. We propose to test the prediction that autism-related genes determine this elaborate spine structure, in which case the IO, because of its simplicity and accessibility, will provide a powerful model for investigation of critical periods and convergence between models of autism.
'Online data capture for genetic causes of autism and intellectual disability' (Andrew Stanfield)
Research question: The objective of the proposed project is to develop an online platform allowing clinical data collection from widely distributed populations with rare genetic neurodevelopmental conditions. Specifically we aim to: Establish engaged cohorts of affected families; Collect phenotypic data and consent for biological sampling; Create a dedicated portal to host future online clinical research. Initial platform testing will be with individuals who have fragile X syndrome, then expanded to other genetic neurodevelopmental conditions.
'Juvenile development of interactions between hippocampus and medial prefrontal cortex in a rat model of Fragile X Syndrome (FXS)' (Emma Wood)
Research question: Using in-vivo electrophysiological recordings from awake behaving animals, we aim to explore the developmental trajectory of HPC-mPFC network and identify neurophysiological signatures of its maturation. This will allow us to characterise periods of elevated neuronal plasticity which may represent important time windows for therapeutic intervention.
'Establishment of a SIDB rodent EEG core' (Alfredo Gonzalez Sulser)
Research question: We will establish an electroencephalography (EEG) rodent core facility for the SIDB community to enable world-class research into the mechanims underlying autism. SIDB researchers will be able to record from their models to assess network dyanimcs, sleep and seizure activity. The facility will provide assistance with training, surgery, recording and analysis in EEG techniques. Software will be developed to quickly analyse data. The core will permit big-picture collaborations to investigate EEG convergence across models.
'Whole brain imaging for identification of circuit deficits in ASD models' (Matt Nolan)
Research question: To take an unbiased approach to identifying neuronal populations whose activity during behavior is altered in ASD models. Initial goals will be to establish brain-wide patterns of activity at cellular resolution in a selected ASD model in one or two behaviors. A longer-term goal will be to evaluate model stratification based on behavioral activation of neurons and /or long-range neuronal connectivity. These goals will be achieved by capitalizing on recently developed optical clearing and imaging methodologies.
'Investigating whether the 16p11.2 microdeletion selectively targets the developmental trajectory of interneurons (Tom Pratt)
Research question: Pilot bioinformatics analysis classified cells in developing human foetal cerebral cortex into different types and found that developing interneurons exhibit enriched expression of monogenic autism risk genes suggesting the hypothesis that interneurons represents a convergent target for Autism with a genetic basis. The 16p11.2 microdeletion is a common polygenic Autism risk factor and similar bioinformatics analysis suggests that the developing interneurons are disproportionately vulnerable to the 16p11.2 microdeletion bolstering our notion of genetic convergence and prompting us to initiate an investigation into the consequences of the 16p11.2 microdeletion on the developmental trajectory of interneurons.
'Modelling the role of the primary cilia gene CEP41 in autism spectrum disorder using human cortical organoids' (Thomas Theil)
Research question: Primary cilia act as signaling hubs during development and mutations in severel ciliary genes have been implicated in autism spectrum disorders (ASD) but their role in ASD pathogenesis remains unknown. Here, we propose to address such novel ciliary roles by investigating the effects of ASD patient-specific mutations in the CEP41 ciliary gene on the development of cortical projection and interneurons using human cortical organoids.
'SIDB vector core to support basic and translational neurodevelopmental support' (Stuart Cobb)
Research goal: To establish a vector lab to support activities in basic and translational neuroscience research. The application of AAV vectors to deliver genetic therapies is a rapidly evolving field and in Edinburgh we currently lack the provision to generate research grade vector of sufficient quality, quantity and concentration for most translational research in neurological disorders.
'Activity-dependent bulk endocytosis dysfunction in Autism Spectrum Disorders: Cause or Consequence?' (Mike Cousin)
Research question: In previous work we have shown convergance around dysfunction in activity-dependent bulk endocytosis (ADBE) across six independent rat models of autism spectrum disorders (ASDs). However, a key unanswered question remains – is ADBE dysfunction a cause of ASD or consequence of this diverse set of mutations? This is a urgent question to address, since it will determine how ADBE should be manipulated as a potential future therapy.
'Sleep disruption in SYNGAP1-related Intellectual Disability' (Lauren Mizen)
Research question: Primary research question - Can the study of sleep in SYNGAP1-related intellectual disability identify biomarkers that can be used in future experimental medicine and clinical trials? Secondary questions – 1. Are the sleep-related seizures, differences in sleep architecture and neuronal connectivity identified in preliminary SynGAP rat data also present in people with SYNGAP1-related intellectual disability? 2. Are there diagnosable sleep or circadian rhythm disorders in the human participants?
'Cardiovascular measures to probe pathophysiology in rodent models of autism spectrum disorders' (Sally Till)
Research question: In addition to cognitive and behavioural symptoms, individuals with autism spectrum disorders (ASDs) have higher than expected rates of co-occurring medical conditions including abnormal regulation of cardiovascular measures. The aim of this project is to determine if these measures are similarly affected in rodent models of ASDs with the view to developing them as a potential translational biomarker to better diagnose and/or assess potential treatments for these disorders.
'Characterising and manipulating distributed cerebello-midbrain circuits in a rat model of SYNGAP1 haploinsufficiency: a role in fear extinction learning?' (Thomas Watson)
Research question: Are cerebello-midbrain networks involved in fear extinction deficits observed in Syngap+/ΔGAP rats?To address this question, we will conduct high-density neural network screening to identify task-related neural correlates/dysfunction within the cerebellum,and other key regions of the fear circuit, during acquisition and extinction of fear memories.Based upon these observations, we will use virally-guided optogenetics to manipulate target pathways during specific task stages in an attempt to rescue fear extinction in Syngap+/ΔGAP rats.
'The Mechanisms Behind Absence Seizures and their Effect on the Development of Autism and Intellectual Dissability Phenotypes in the Syngap+/ΔGAP Rat Model' (Alfredo Gonzalez Sulser)
Research question: Do seizures contribute to autism (ASD) severity? Rats heterozygous for the C2/GAP domain deletion (Syngap+/ΔGAP)display absence seizures that may worsen ASD phenotypes, such as deficits insleep and social behavior. We will determine whether seizure blockade reverses ASD phenotypes and if this is dependent on animaldevelopmental stage. We will also assess whether thalamicnuclei drive absence seizures and whether they can be specifically targeted to blockSWDs andpositively influence ASD phenotypes.
'Mechanisms of axon initial segment plasticity and their implications for autism spectrum disorders' (Peter Brophy)
Research question: The axon initial segment (AIS) regulates neuronal excitability. Neuronal hyperexcitability is a key feature of animal models of Fragile-X syndrome and recent evidence suggests that reduced synaptic activity in FMR1-/y mice promotes both AIS elongation and hyperexcitability. We hypothesize that loss of FMRP promotes aberrant recruitment of AIS membrane proteins. This study should not only contribute to an understanding of the mechanisms of AIS plasticity but also identify potential new targets in Autism Spectrum Disorder.
'The generation and validation of re-expression and conditional knock-out rat models for key SFARI genes' (Katie Paton)
Research question: To explore whether the disruption of key SFARI genes in rats during brain development causes irrevocable damage to neurons and whether persistent expression of the gene is needed to maintain of neuronal function.
'Hippocampal function in a rat model of GRIN2B haploinsufficiency' (Emma Wood)
Research question: Heterozygous loss of function mutations in GRIN2B, which codes for the GluN2B subunit of the NMDA receptor, are associated with neurodevelopmental disorders including ASD/ID. The GluN2B subunit plays key roles both in neuronal development and circuit formation, and in learning, memory and synaptic plasticity. A key unanswered question is the extent to which GRIN2Bhaploinsufficiency affects neuronal and circuit function, plasticity and memory. We will test this in a new Grin2b+/-rat model.
'Investigation of tactile and pain phenotypes in rodent models of autism spectrum disorders' (Carole Torsney)
Research question: Is there altered spinal processing of tactile and pain inputs in rodent models of autism spectrum disorders that is reflected in altered spinal reflex behaviours? Specifically, does SynGAP haploinsufficiency cause a deficit in spinal processing of tactile inputs?
Investigating the Function of ASXL3 to Determine the Molecular Basis of Bainbridge–Ropers Syndrome (Rob Illingworth)
Research question: What are the molecular mechanisms that underpin Bainbridge–Ropers syndrome (BRPS), an ASD that results from aberrant chromatin regulation? The function of ASXL3, the chromatin modifier protein whose deficiency gives rise to BRPS, is largely unknown. Using in vitro models of brain development, in combination with inducible degradation strategies, I will assess the molecular and cellular impact of ASXL3 deficiency. This will provide key insight into the function of ASXL3 during normal brain development and provide an important basis for understanding the molecular aetiology of BRPS. Importantly, this approach will allow for restoration of ASXL3 function, a crucial step in determining if clinically relevant rescue experiments might one day be viable in the context of BRPS and disorders of abnormal chromatin regulation.