A5087802295- Neuroscience and Neuropharmacology Research
- Genetics and Neurodevelopmental Disorders
- Autism Spectrum Disorder Research
- Neural dynamics and brain function
- Neurogenesis and neuroplasticity mechanisms
- Cellular transport and secretion
- Functional Brain Connectivity Studies
- Pluripotent Stem Cells Research
- Lipid Membrane Structure and Behavior
- Advanced Fluorescence Microscopy Techniques
- Photoreceptor and optogenetics research
- CRISPR and Genetic Engineering
- Developmental Biology and Gene Regulation
- Cannabis and Cannabinoid Research
- EEG and Brain-Computer Interfaces
- Retinal Development and Disorders
- Axon Guidance and Neuronal Signaling
- Neuroscience and Neural Engineering
- Optical Coherence Tomography Applications
- Cellular Mechanics and Interactions
- Advanced Neuroimaging Techniques and Applications
- Wnt/β-catenin signaling in development and cancer
- Memory and Neural Mechanisms
- Pancreatic function and diabetes
- Cancer-related gene regulation
NeuroDevelopment Center
2024
King's College London
2012-2024
Guy's Hospital
2017
FENS Kavli Network of Excellence
2017
King's College - North Carolina
2013
The Francis Crick Institute
2007
National Hospital for Neurology and Neurosurgery
1999
University College London
1999
University of Cambridge
1993
Shank3 is a structural protein found predominantly at the postsynaptic density. Mutations in SHANK3 gene have been associated with risk for autism spectrum disorder (ASD). We generated induced pluripotent stem cells (iPSCs) from control individuals and human donors ASD carrying microdeletions of SHANK3. In addition, we used Zinc finger nucleases to generate isogenic knockout embryonic (ES) cell lines. differentiated into either cortical or olfactory placodal neurons. show that...
Down syndrome (DS) is a genetic disorder arising from the presence of third copy human chromosome 21 (Hsa21). Recently, O’Doherty and colleagues in an earlier study generated new mouse model DS (Tc1) that carries almost complete Hsa21. Since most common cause mental retardation, we have undertaken detailed analysis cognitive function synaptic plasticity Tc1 mice. Here show mice impaired spatial working memory (WM) but spared long-term reference (RM) Morris watermaze. Similarly, are...
Mature presynaptic terminals release neurotransmitter both in response to activity and spontaneously. We found that axons of rat hippocampal neurons initially show very high levels exclusively spontaneous release, which progressively switches over the mature phenotype during synapse formation. These two modes vesicle cycling derive from distinct pools throughout development initiation activity-dependent was independent postsynaptic contacts, suggesting it is an autonomous event.
Heterozygous mutation of chromodomain helicase DNA binding protein 8 (CHD8) is strongly associated with autism spectrum disorder (ASD) and results in dysregulated expression neurodevelopmental synaptic genes during brain development. To reveal how these changes affect ASD-associated cortical circuits, we studied transmission the prefrontal cortex a haploinsufficient Chd8 mouse model. We report profound alterations to both excitatory inhibitory onto deep layer projection neurons, resulting...
Spontaneous neurotransmitter release is a core element of synaptic communication in mature neurons, but despite exceptionally high levels spontaneous vesicle cycling occurring developing axons, little known its function during this period. We now show that high-level, axonal the glutamate can signal at long range to NMDA receptors on dendrites, prior synapse formation and, indeed, axodendritic contact. Blockade signaling early period leads reduction dendritic arbor complexity, indicating an...
Neurexin 1α mutations are strongly associated with neurodevelopmental disorders such as autism spectrum and schizophrenia in humans. Studies using the knock-out mouse have showed behavioral abnormalities of relevance to these baseline deficits excitatory synaptic function been described. However, little is known about effect deletion on behavior during development. This study examined effects across a range developmental time points determine whether potential follow trajectory. Pups lacking...
The cost of 3D printing has reduced dramatically over the last few years and is now within reach many scientific laboratories. This work presents an example how can be applied to development custom laboratory equipment that specifically adapted for use with novel brain tissue clearing technique, CLARITY. A simple, freely available online software tool was used, along consumer-grade equipment, produce a slicing chamber combined antibody staining imaging chamber. Using standard printers we...
The histone lysine demethylase KDM5B is implicated in recessive intellectual disability disorders, and heterozygous, protein-truncating variants are associated with reduced cognitive function the population. KDM5 family of demethylases has developmental homeostatic functions brain, some which appear to be independent activity. To determine hippocampus-dependent learning memory, we first studied male female mice homozygous for a Kdm5b Δ ARID allele that lacks ARID/ exhibited hyperactivity...
The midbrain-hindbrain boundary (MHB) acts as an organiser/signalling centre to pattern tectal and cerebellar compartments. Cells in adjacent compartments must be distinct from each other for formation occur at the interface. Here we have identified leucine-rich repeat (LRR) neuronal 1 (Lrrn1) protein a key regulator of this process chick. Lrrn family is orthologous Drosophila tartan/capricious (trn/caps) family. Differential expression trn/caps promotes affinity difference between number...
The Drosophila leucine-rich repeat proteins Tartan (TRN) and Capricious (CAPS) mediate cell affinity differences during compartition of the wing imaginal disc. This study aims to identify characterize expression a chick orthologue TRN/CAPS examine its potential function in relation compartment boundaries vertebrate central nervous system.We identified complementary DNA clone encoding Leucine-rich neuronal 1 (Lrrn1), single-pass transmembrane protein with 12 extracellular repeats most closely...
The controversy continues as to whether new neurons are born in adult human hippocampus.
Abstract Introduction Conditionally immortalised human neural progenitor cells (hNPCs) represent a robust source of native to investigate physiological mechanisms in both health and disease. However, order recognise the utility such cells, it is critical determine whether they retain characteristics their tissue origin generate appropriate cell types upon differentiation. To this end, we have characterised conditionally immortalised, cortically-derived, NPC line, CTX0E16, investigating...
Of the many genetic mutations known to increase risk of autism spectrum disorder, a large proportion cluster upon synaptic proteins. One such family presynaptic proteins are neurexins (NRXN), and recent mouse evidence has suggested causative role for NRXN2 in generating altered social behaviours. Autism been conceptualised as disorder atypical connectivity, yet how single-gene affect connectivity remains under-explored. To attempt address this, we have developed quantitative analysis...
Abstract The rules governing neural circuit formation in mammalian central nervous systems are poorly understood. NMDA receptors involved synaptic plasticity mechanisms mature neurons, but their contribution to and dendritic maturation remains controversial. Using pharmacological genetic interventions disrupt receptor signaling hippocampal CA1 pyramidal neurons vitro vivo , we identify an early critical window for a synapse-specific function wiring Schaffer collateral connections...
Deletions and mutations in the SHANK3 gene are strongly associated with autism spectrum disorder underlie autism-associated Phelan–McDermid syndrome. is a scaffolding protein found at post-synaptic membrane of excitatory neurons. Single-molecule fluorescence in-situ hybridization (smFISH) allows visualization single mRNA transcripts vitro. Here we perform quantify smFISH human inducible pluripotent stem cell (hiPSC)-derived cortical neurons, targeting transcript. Both conventional...
During the third trimester of human gestation, structure and function fetal brain is developing rapidly, laying foundation for its connectivity framework across lifespan. this juncture, resting state functional MRI can be used to identify networks (RSNs) which mature gestation resemble canonical RSNs at full term. However, emergence finer grain organisation within these in unknown. Using in-utero fMRI, we performed connectopic mapping analysis explore presence gradients 11 cortical RSNs,...
Abstract Background Capricious is a Drosophila adhesion molecule that regulates specific targeting of subset motor neurons to their muscle target. We set out identify whether one its vertebrate homologues, Lrrn2, might play an analogous role in the chick. Results have shown Lrrn2 expressed from early development prospective rhombomere 4 (r4) chick hindbrain. Subsequently, expression hindbrain becomes restricted group neurons, branchiomotor r4, and pre-muscle target, second branchial arch...
Abstract Heterozygous mutation of chromodomain helicase DNA binding protein 8 ( CHD8 ) is strongly associated with autism spectrum disorder (ASD) and results in dysregulated expression neurodevelopmental synaptic genes during brain development. To reveal how these changes affect ASD-associated cortical circuits, we studied transmission the prefrontal cortex a haploinsufficient Chd8 mouse model. We report profound alterations to both excitatory inhibitory onto deep layer projection neurons,...