Agency: Cordis | Branch: FP7 | Program: CP-IP | Phase: HEALTH-2009-2.2.1-1 | Award Amount: 15.81M | Year: 2010
Signalling at nerve cell synapses - a key determinant of all aspects of brain function - depends on the function of hundreds of synaptic proteins and their interactions. Numerous recent studies showed that a wide range of neurological and psychiatric diseases are synaptopathies whose onset and progression are due to mutations of synaptic proteins and subsequent synaptic dysfunctions. EUROSPIN will pursue a multilevel systems biology approach to determine mechanistic relationships between mutations of synaptic proteins and neurological and psychiatric diseases, and to develop new diagnostic tools and therapies. Our concept is based on the current knowledge of disease genes, which we will continuously extend with new human genetic data and complement with large-scale screens of mutant mice in order to identify and characterize disease-relevant mutations in synaptic proteins and corresponding mouse models. Proteomic tools will be used to analyse the protein components of synapses, and protein interaction networks of synaptic disease gene products will be mapped systematically. In parallel, smart libraries will be employed to develop small molecules for perturbing the functions and interactions of disease gene products. Functional models of disease-relevant protein networks will be generated and used to formulate hypotheses as to how specific mutations might affect synaptic physiology and network function, and thus cause disease. These hypotheses will initially be tested in reduced systems by novel physiological and imaging methods. Well-validated disease gene products, the consequences of their dysfunction in disease, and therapeutic modifications of their dysfunction will then be studied in mouse models in vivo, applying novel electrophysiological, imaging, and behavioural techniques. The combined information obtained in the EUROSPIN program will be used for the development of new diagnostic tools and therapeutic interventions that can be tested in patients.
Agency: Cordis | Branch: FP7 | Program: CPCSA | Phase: ICT-2013.9.9 | Award Amount: 72.73M | Year: 2013
Understanding the human brain is one of the greatest challenges facing 21st century science. If we can rise to the challenge, we can gain profound insights into what makes us human, develop new treatments for brain diseases and build revolutionary new computing technologies. Today, for the first time, modern ICT has brought these goals within sight. The goal of the Human Brain Project, part of the FET Flagship Programme, is to translate this vision into reality, using ICT as a catalyst for a global collaborative effort to understand the human brain and its diseases and ultimately to emulate its computational capabilities. The Human Brain Project will last ten years and will consist of a ramp-up phase (from month 1 to month 36) and subsequent operational phases.\nThis Grant Agreement covers the ramp-up phase. During this phase the strategic goals of the project will be to design, develop and deploy the first versions of six ICT platforms dedicated to Neuroinformatics, Brain Simulation, High Performance Computing, Medical Informatics, Neuromorphic Computing and Neurorobotics, and create a user community of research groups from within and outside the HBP, set up a European Institute for Theoretical Neuroscience, complete a set of pilot projects providing a first demonstration of the scientific value of the platforms and the Institute, develop the scientific and technological capabilities required by future versions of the platforms, implement a policy of Responsible Innovation, and a programme of transdisciplinary education, and develop a framework for collaboration that links the partners under strong scientific leadership and professional project management, providing a coherent European approach and ensuring effective alignment of regional, national and European research and programmes. The project work plan is organized in the form of thirteen subprojects, each dedicated to a specific area of activity.\nA significant part of the budget will be used for competitive calls to complement the collective skills of the Consortium with additional expertise.
Agency: Cordis | Branch: FP7 | Program: BSG-SME | Phase: SME-1 | Award Amount: 1.89M | Year: 2009
The project PharMEA is based on the technology platform of multi-electrode arrays, which have been widely used for electrophysiological experiments on neuronal and cardiac tissues. Some of the key advantages of MEA technology include ease of use, non-invasive measurements and simultaneous multi-site recording & stimulation capability. Despite these key advantages, MEA technology utilization has remained largely confined in academic research institutions, primarily due to the low throughput of currently available MEA-based tools. The PharMEA project addresses these shortcomings by developing novel MEA tools and applications that will significantly increase throughput of MEA experiments, facilitate MEA experiments on various culture models, as well as associated applications tailored for the drug discovery industry. Specifically, the new MEA tools will increase the number of channels or measurement sites for simultaneous recording and stimulation from about 120 channels today to 1024 channels, along with the corresponding intelligent data handling and processing strategies. Furthermore, the PharMEA project will develop and automate biological assay protocols that are common in ion-channel based drug discovery activities, as we this will add significant value to and bring out the benefit of the proposed tools. Altogether, the results of this project will accelerate the uptake of MEA tools in the drug discovery industry, thereby significantly increasing the market opportunity and competitive edge of the various sponsoring SMEs in the lucrative drug discovery industry.
Agency: Cordis | Branch: FP7 | Program: CP-IP | Phase: HEALTH-2009-2.1.1-1 | Award Amount: 16.03M | Year: 2010
Mutations in about 400 different genes have been associated with Cognitive Disorders (CD), such as mental retardation, autism, neurodegenerative disorders, and psychiatric disorders. Whereas CD impose a major medical and socio-economical problem, there are no systematic studies that aim to provide insight into common mechanisms in CD. We propose a systems biology approach to gain insight into common mechanisms leading to cognitive impairment: (1) Identification of genes involved in cognitive disorders. Despite considerable progress in the identification of genes underlying CD, the majority of causative genes in CD remain unidentified. Therefore, our first objective is to identify new genes causative of CD by implementing high-throughput strategies. (2) Elucidation of molecular networks that are commonly disrupted in CD. Recent genetic and neurobiological research revealed evidence for a number of molecular and cellular pathways that are shared by the various genetic CDs. Prominent examples are Rho GTPase-related genes and genes that regulate chromatin structure/function (epigenetics) associated with mental retardation and autism. Our second objective is to systematically explore this concept by elucidation of molecular networks using functional genomics strategies in genetic models that are the cornerstone of neuroscience, such as mouse and fruit fly. (3) Identify genetic modifiers and small compounds that modulate the disease phenotype. Our third objective is to resolve the molecular underpinnings of the large degree of clinical variability that is typical for all types of CD, even among patients carrying identical gene mutations. Genetic modifier screens in cultured primary neurons as well as in available Drosophila models for CD will be used to reveal phenotypically relevant genetic interactions and molecular networks. Moreover, drug screens shall be conducted in fly and cellular models for CD, which will lead to pharmacological rescue of mouse models.
PubMed | Heriot - Watt University, Technical University of Madrid, University of Edinburgh, Synome Ltd and University of Cambridge
Type: | Journal: Scientific reports | Year: 2016
The molecular features of synapses in the hippocampus underpin current models of learning and cognition. Although synapse ultra-structural diversity has been described in the canonical hippocampal circuitry, our knowledge of sub-synaptic organisation of synaptic molecules remains largely unknown. To address this, mice were engineered to express Post Synaptic Density 95 protein (PSD95) fused to either eGFP or mEos2 and imaged with two orthogonal super-resolution methods: gated stimulated emission depletion (g-STED) microscopy and photoactivated localisation microscopy (PALM). Large-scale analysis of ~100,000 synapses in 7 hippocampal sub-regions revealed they comprised discrete PSD95 nanoclusters that were spatially organised into single and multi-nanocluster PSDs. Synapses in different sub-regions, cell-types and locations along the dendritic tree of CA1 pyramidal neurons, showed diversity characterised by the number of nanoclusters per synapse. Multi-nanocluster synapses were frequently found in the CA3 and dentate gyrus sub-regions, corresponding to large thorny excrescence synapses. Although the structure of individual nanoclusters remained relatively conserved across all sub-regions, PSD95 packing into nanoclusters also varied between sub-regions determined from nanocluster fluorescence intensity. These data identify PSD95 nanoclusters as a basic structural unit, or building block, of excitatory synapses and their number characterizes synapse size and structural diversity.
PubMed | Synome Ltd., University of Edinburgh, Radboud Institute for Molecular Life science, Donders Institute for Brain and University of Cambridge
Type: | Journal: Scientific reports | Year: 2017
Heterozygous mutations or deletions of the human Euchromatin Histone Methyltransferase 1 (EHMT1) gene are the main causes of Kleefstra syndrome, a neurodevelopmental disorder that is characterized by impaired memory, autistic features and mostly severe intellectual disability. Previously, Ehmt1
Horner A.E.,Synome Ltd. |
Horner A.E.,University of Cambridge |
Heath C.J.,University of Cambridge |
Hvoslef-Eide M.,University of Cambridge |
And 8 more authors.
Nature Protocols | Year: 2013
An increasingly popular method of assessing cognitive functions in rodents is the automated touchscreen platform, on which a number of different cognitive tests can be run in a manner very similar to touchscreen methods currently used to test human subjects. This methodology is low stress (using appetitive rather than aversive reinforcement), has high translational potential and lends itself to a high degree of standardization and throughput. Applications include the study of cognition in rodent models of psychiatric and neurodegenerative diseases (e.g., Alzheimer's disease, schizophrenia, Huntington's disease, frontotemporal dementia), as well as the characterization of the role of select brain regions, neurotransmitter systems and genes in rodents. This protocol describes how to perform four touchscreen assays of learning and memory: visual discrimination, object-location paired-associates learning, visuomotor conditional learning and autoshaping. It is accompanied by two further protocols (also published in this issue) that use the touchscreen platform to assess executive function, working memory and pattern separation. © 2013 Nature America, Inc. All rights reserved.
Mar A.C.,University of Cambridge |
Horner A.E.,University of Cambridge |
Horner A.E.,Synome Ltd. |
Nilsson S.R.O.,University of Cambridge |
And 6 more authors.
Nature Protocols | Year: 2013
This protocol details a subset of assays developed within the touchscreen platform to measure various aspects of executive function in rodents. Three main procedures are included: extinction, measuring the rate and extent of curtailing a response that was previously, but is no longer, associated with reward; reversal learning, measuring the rate and extent of switching a response toward a visual stimulus that was previously not, but has become, associated with reward (and away from a visual stimulus that was previously, but is no longer, rewarded); and the 5-choice serial reaction time (5-CSRT) task, gauging the ability to selectively detect and appropriately respond to briefly presented, spatially unpredictable visual stimuli. These protocols were designed to assess both complementary and overlapping constructs including selective and divided visual attention, inhibitory control, flexibility, impulsivity and compulsivity. The procedures comprise part of a wider touchscreen test battery assessing cognition in rodents with high potential for translation to human studies. © 2013 Nature America, Inc. All rights reserved.
Balemans M.C.M.,Radboud University Nijmegen |
Nadif kasri N.,Radboud University Nijmegen |
Kopanitsa M.V.,Synome Ltd |
Afinowi N.O.,Synome Ltd |
And 13 more authors.
Human Molecular Genetics | Year: 2013
Euchromatin histone methyltransferase 1 (EHMT1) is a highly conserved protein that catalyzes mono- and dimethylation of histone H3 lysine 9, thereby epigenetically regulating transcription. Kleefstra syndrome (KS), is caused by haploinsufficiency of the EHMT1 gene, and is an example of an emerging group of intellectual disability (ID) disorders caused by genes encoding epigenetic regulators of neuronal gene activity. Little is known about the mechanisms underlying this disorder, prompting us to study the Euchromatin histone methyltransferase 1 heterozygous knockout (Ehmt1+/-) mice as a model for KS. In agreement with the cognitive disturbances observed in patients with KS, we detected deficits in fear extinction learning and both novel and spatial object recognition in Ehmt1+/- mice. These learning and memory deficits were associated with a significant reduction in dendritic arborization and the number of mature spines in hippocampal CA1 pyramidal neurons of Ehmt1+/- mice. In-depth analysis of the electrophysiological properties of CA3-CA1 synapses revealed no differences in basal synaptic transmission or theta-burst induced long-term potentiation (LTP). However, paired-pulse facilitation (PPF) was significantly increased in Ehmt1+/- neurons, pointing to a potential deficiency in presynaptic neurotransmitter release. Accordingly, a reduction in the frequency of miniature excitatory post-synaptic currents (mEPSCs) was observed in Ehmt1+/- neurons. These data demonstrate that Ehmt1 haploinsufficiency in mice leads to learning deficits and synaptic dysfunction, providing a possible mechanism for the ID phenotype in patients with KS. © The Author 2012. Published by Oxford University Press. All rights reserved.