A5007167675- Genetics and Neurodevelopmental Disorders
- Particle Detector Development and Performance
- Neuroscience and Neuropharmacology Research
- Autism Spectrum Disorder Research
- Particle physics theoretical and experimental studies
- Neurogenesis and neuroplasticity mechanisms
- Radiation Detection and Scintillator Technologies
- Cellular transport and secretion
- Congenital heart defects research
- Distributed and Parallel Computing Systems
- Retinal Development and Disorders
- High-Energy Particle Collisions Research
- Receptor Mechanisms and Signaling
- Ubiquitin and proteasome pathways
- Neurobiology and Insect Physiology Research
- Axon Guidance and Neuronal Signaling
- CCD and CMOS Imaging Sensors
- Genomic variations and chromosomal abnormalities
- Neuroinflammation and Neurodegeneration Mechanisms
- Mitochondrial Function and Pathology
- Photoreceptor and optogenetics research
- RNA modifications and cancer
- Memory and Neural Mechanisms
- Neural dynamics and brain function
- Plant and Biological Electrophysiology Studies
University of Edinburgh
2016-2025
Institute for Stem Cell Biology and Regenerative Medicine
2015-2025
Discovery Centre
2019-2025
Simons Initiative for the Developing Brain
2021-2025
UK Dementia Research Institute
2022-2024
Maxwell Institute for Mathematical Sciences
2023-2024
University of Wuppertal
2006-2023
National Centre for Biological Sciences
2014-2022
Tata Institute of Fundamental Research
2022
Simons Foundation
2021
Pharmacological activation of the GABA B receptor with arbaclofen in a mouse model fragile X syndrome corrects neuronal defects associated disease.
Alterations of the N-methyl-d-aspartate receptor (NMDAR) subunit GluN2A, encoded by GRIN2A, have been associated with a spectrum neurodevelopmental disorders prominent speech-related features, and epilepsy. We performed comprehensive assessment phenotypes standardized questionnaire in 92 previously unreported individuals GRIN2A-related disorders. Applying criteria American College Medical Genetics Genomics to all published variants yielded 156 additional cases pathogenic or likely resulting...
Mutations in C9ORF72 are the most common cause of familial amyotrophic lateral sclerosis (ALS). Here, through a combination RNA-Seq and electrophysiological studies on induced pluripotent stem cell (iPSC)-derived motor neurons (MNs), we show that increased expression GluA1 AMPA receptor (AMPAR) subunit occurs MNs with mutations leads to Ca2+-permeable AMPAR results enhanced selective MN vulnerability excitotoxicity. These deficits not found iPSC-derived cortical abolished by...
Abstract Alzheimer’s disease (AD) alters astrocytes, but the effect of Aß and Tau pathology is poorly understood. TRAP-seq translatome analysis astrocytes in APP/PS1 ß-amyloidopathy MAPT P301S tauopathy mice revealed that only influenced expression AD risk genes, both pathologies precociously induced age-dependent changes, had distinct overlapping signatures found human post-mortem astrocytes. Both an astrocyte signature involving repression bioenergetic translation machinery, induction...
Monoclonal antibody Cat-301 recognizes a chondroitin sulfate proteoglycan (CSPG) expressed on the extracellular surface of cell bodies and proximal dendrites specific subsets neurons in many areas mammalian CNS, including cat visual cortex. The CSPG is first detected at close critical period development, during which pattern neuronal activity determines mature synaptic circuitry phenotype. In cortex, dark-rearing from birth prolongs duration attenuates expression antigen, implicating...
It is currently unclear whether the GluN2 subtype influences NMDA receptor (NMDAR) excitotoxicity. We report that toxicity of NMDAR-mediated Ca2+ influx differentially controlled by cytoplasmic C-terminal domains GluN2B (CTD2B) and GluN2A (CTD2A). Studying effects acute expression GluN2A/2B-based chimeric subunits with reciprocal exchanges their CTDs revealed CTD2B enhances NMDAR toxicity, compared to CTD2A. Furthermore, vulnerability forebrain neurons in vitro vivo NMDAR-dependent lowered...
The ATLAS collaboration will upgrade its semiconductor pixel tracking detector with a new Insertable B-layer (IBL) between the existing and vacuum pipe of Large Hadron Collider. extreme operating conditions at this location have necessitated development radiation hard sensor technologies front-end readout chip, called FE-I4. Planar sensors 3D been investigated to equip layer, prototype modules using FE-I4A fabricated characterized 120 GeV pions CERN SPS 4 positrons DESY, before after module...
Recent advances in techniques for manipulating genomes have allowed the generation of transgenic animals other than mice. These new models enable cross-mammalian comparison neurological disease from core cellular pathophysiology to circuit and behavioural endophenotypes. Moreover they will us directly test whether common dysfunction or outcomes a genetic mutation are more conserved across species. Using rat model Fragile X Syndrome, we report that Fmr1 knockout (KO) rats exhibit elevated...
Excessive mRNA translation downstream of group I metabotropic glutamate receptors (mGlu1/5) is a core pathophysiology fragile X syndrome (FX); however, the differentially translating mRNAs that contribute to altered neural function are not known. We used ribosome affinity purification (TRAP) and RNA-seq identify mistranslating in CA1 pyramidal neurons FX mouse model (Fmr1-/y) hippocampus, which exhibit exaggerated mGlu1/5-induced long-term synaptic depression (LTD). In these neurons, we find...
Brief, early treatments with lovastatin provide long-lasting rescue of associative memory deficits in a rat model Fragile X.
Abstract In multiple sclerosis (MS), a chronic demyelinating disease of the central nervous system, neurodegeneration is detected early in course and associated with long-term disability patients. Neurodegeneration linked to both inflammation demyelination, but its exact cause remains unknown. This gap knowledge contributes current lack treatments for neurodegenerative phase MS. Here we ask if MS affects specific neuronal components it result demyelination. Neuropathological examination...
Mutations in SYNGAP1 are a common genetic cause of intellectual disability (ID) and risk factor for autism. encodes synaptic GTPase-activating protein (GAP) that has both signaling scaffolding roles. Most pathogenic variants predicted to result haploinsufficiency. However, some affected individuals carry missense mutations its calcium/lipid binding (C2) GAP domains, suggesting many clinical features from loss functions carried out by these domains. To test this hypothesis, we targeted the...
Abstract Background Mutations in the X-linked gene cyclin-dependent kinase-like 5 ( CDKL5 ) cause a severe neurological disorder characterised by early-onset epileptic seizures, autism and intellectual disability (ID). Impaired hippocampal function has been implicated other models of monogenic forms spectrum disorders ID is often linked to epilepsy behavioural abnormalities. Many individuals with deficiency (CDD) have null mutations complete loss protein, therefore current study we used...
Abstract Background The key pathological mechanisms underlying autism spectrum disorder (ASD) remain relatively undetermined, potentially due to the heterogenous nature of condition. Targeted studies a series monogenic ASDs have revealed postsynaptic dysfunction as central conserved mechanism. Presynaptic is emerging an additional disease locus in neurodevelopmental disorders; however, it unclear whether this drives ASD or adaptation altered brain microenvironment. Methods To differentiate...
Strabismic humans usually experience powerful suppression of vision in the nonfixating eye. In an attempt to demonstrate physiological correlates such suppression, we recorded from primary visual cortex cats with surgically induced squint and studied responses neurons drifting gratings different orientation, spatial frequency, contrast two eyes. Only 1 50 apparently monocular cells showed any evidence remaining, subliminal excitatory input "silent" eye when eyes were stimulated similar even...
Fragile X syndrome (FXS) is the most common inherited form of intellectual disability and results from loss fragile mental retardation protein (FMRP). Many X-related cognitive behavioral features emerge during childhood are associated with abnormal synaptic cellular organization cerebral cortex. Identifying roles FMRP in cortical development will provide a basis for understanding pathogenesis syndrome. However, how influences developmental trajectory maturation remains unclear. We took...
Alternative promoter usage and alternative splicing enable diversification of the transcriptome. Here we demonstrate that function Synaptic GTPase-Activating Protein (SynGAP), a key synaptic protein, is determined by combination its amino-terminal sequence with carboxy-terminal sequence. 5′ rapid amplification cDNA ends primer extension show different N-terminal protein sequences arise through are regulated activity postnatal age. Heterogeneity in C-terminal arises splicing. Overexpression...
Previous studies have hypothesized that diverse genetic causes of intellectual disability (ID) and autism spectrum disorders (ASDs) converge on common cellular pathways. Testing this hypothesis requires detailed phenotypic analyses animal models with mutations accurately reflect those seen in the human condition (i.e., structural validity) which produce phenotypes mirror ID/ASDs face validity). We show SynGAP haploinsufficiency, ID co-occurring ASD humans, mimics occludes synaptic...
Mutations in the X-linked Cyclin-Dependent Kinase-Like 5 gene (CDKL5) cause early onset infantile spasms and subsequent severe developmental delay affected children. Deleterious mutations have been reported to occur throughout CDKL5 coding region. Several studies point a complex structure terms of exon usage transcript expression. Improvements molecular diagnosis more extensive research into neurobiology pathophysiology disorders necessitate an updated analysis gene. In this study, we...
Abstract Rodent-based studies have shown that the membrane properties of oligodendrocytes play prominent roles in their physiology and shift markedly during maturation from oligodendrocyte precursor cell (OPC) stage. However, conservation these processes human remains unknown, despite dysfunction being implicated neurodegenerative diseases such as multiple sclerosis (MS) amyotrophic lateral (ALS). Here, we defined derived pluripotent stem cells they mature OPC stage, identified strong...