ORCID Profile
0000-0002-2947-1557
Current Organisation
University of Aberdeen
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Publisher: Springer Science and Business Media LLC
Date: 09-2012
DOI: 10.1038/NATURE11405
Publisher: Cold Spring Harbor Laboratory
Date: 19-12-2018
DOI: 10.1101/500447
Abstract: How is the information encoded within patterns of nerve impulses converted into erse behavioral responses? To address this question, we conducted the largest genetic study to date of the electrophysiological and behavioral properties of synapses. Postsynaptic responses to elementary patterns of activity in the hippoc al CA1 region were measured in 58 lines of mice carrying mutations in the principal classes of excitatory postsynaptic proteins. A combinatorial molecular mechanism was identified in which distinct subsets of proteins lified or attenuated responses across timescales from milliseconds to an hour. The same mechanism controlled the ersity and magnitude of innate and learned behavioral responses. PSD95 supercomplex proteins were central components of this synaptic machinery. The capacity of vertebrate synapses to compute activity patterns increased with genome evolution and is impaired by disease-relevant mutations. We propose that this species-conserved molecular mechanism converts the temporally encoded information in nerve impulses into the repertoire of innate and learned behavior.
Publisher: Portland Press Ltd.
Date: 22-03-2010
DOI: 10.1042/BST0380445
Abstract: Understanding how cognitive processes including learning, memory, decision making and ideation are encoded by the genome is a key question in biology. Identification of sets of genes underlying human mental disorders is a path towards this objective. Schizophrenia is a common disease with cognitive symptoms, high heritability and complex genetics. We have identified genes involved with schizophrenia by measuring differences in DNA copy number across the entire genome in 91 schizophrenia cases and 92 controls in the Scottish population. Our data reproduce rare and common variants observed in public domain data from & schizophrenia cases, confirming known disease loci as well as identifying novel loci. We found copy number variants in PDE10A (phosphodiesterase 10A), CYFIP1 [cytoplasmic FMR1 (Fragile X mental retardation 1)-interacting protein 1], K+ channel genes KCNE1 and KCNE2, the Down's syndrome critical region 1 gene RCAN1 (regulator of calcineurin 1), cell-recognition protein CHL1 (cell adhesion molecule with homology with L1CAM), the transcription factor SP4 (specificity protein 4) and histone deacetylase HDAC9, among others (see www.genes2cognition.org/SCZ-CNV). Integrating the function of these many genes into a coherent model of schizophrenia and cognition is a major unanswered challenge.
Publisher: Wiley
Date: 20-01-2017
DOI: 10.1111/GBB.12364
Abstract: Behavioural analysis of mice carrying engineered mutations is widely used to identify roles of specific genes in components of the mammalian behavioural repertoire. The reproducibility and robustness of phenotypic measures has become a concern that undermines the use of mouse genetic models for translational studies. Contributing factors include low in idual study power, non-standardized behavioural testing, failure to address confounds and differences in genetic background of mutant mice. We have examined the importance of these factors using a statistically robust approach applied to behavioural data obtained from three mouse mutations on 129S5 and C57BL/6J backgrounds generated in a standardized battery of five behavioural assays. The largest confounding effect was s ling variation, which partially masked the genetic background effect. Our observations suggest that strong interaction of mutation with genetic background in mice in innate and learned behaviours is not necessarily to be expected. We found composite measures of innate and learned behaviour were similarly impacted by mutations across backgrounds. We determined that, for frequently used group sizes, a single retest of a significant result conforming to the commonly used P < 0.05 threshold results in a reproducibility of 60% between identical experiments. Reproducibility was reduced in the presence of strain differences. We also identified a P-value threshold that maximized reproducibility of mutant phenotypes across strains. This study illustrates the value of standardized approaches for quantitative assessment of behavioural phenotypes and highlights approaches that may improve the translational value of mouse behavioural studies.
Publisher: Cold Spring Harbor Laboratory
Date: 19-12-2018
DOI: 10.1101/500389
Abstract: Although molecular mechanisms underpinning specific behaviors have been described, whether there are mechanisms that orchestrate a behavioral repertoire is unknown. To test if the postsynaptic proteome of excitatory synapses could impart such a mechanism we conducted the largest genetic study of mammalian synapses yet undertaken. A repertoire of sixteen innate and learned behaviors was assessed from 290,850 measures in 55 lines of mutant mice carrying targeted mutations in the principal classes of postsynaptic proteins. Each innate and learned behavior used a different combination of proteins. These combinations were comprised of proteins that lified or attenuated the magnitude of each behavioral response. All behaviors required proteins found in PSD95 supercomplexes. We show the vertebrate increase in proteome complexity drove an expansion in behavioral repertoires and generated susceptibility to a wide range of diseases. Our results reveal a molecular mechanism that generates a versatile and complex behavioral repertoire that is central to human behavioral disorders.
Publisher: Springer Science and Business Media LLC
Date: 19-12-2010
DOI: 10.1038/NN.2719
Publisher: Frontiers Media SA
Date: 08-12-2014
Publisher: Public Library of Science (PLoS)
Date: 29-04-2011
Publisher: Public Library of Science (PLoS)
Date: 05-10-2012
Publisher: Springer Science and Business Media LLC
Date: 06-10-2018
Publisher: Elsevier BV
Date: 07-2010
DOI: 10.1016/J.NEURON.2010.06.026
Abstract: A large international consortium reports in Nature on the ersity of genomic changes in families with autism spectrum disorders. Inherited and de novo mutations affecting many genes were discovered implicating disruption to postsynaptic and cellular signaling processes.
Publisher: Springer Science and Business Media LLC
Date: 07-01-2014
DOI: 10.1038/TP.2013.114
Abstract: Differences in general cognitive ability (intelligence) account for approximately half of the variation in any large battery of cognitive tests and are predictive of important life events including health. Genome-wide analyses of common single-nucleotide polymorphisms indicate that they jointly tag between a quarter and a half of the variance in intelligence. However, no single polymorphism has been reliably associated with variation in intelligence. It remains possible that these many small effects might be aggregated in networks of functionally linked genes. Here, we tested a network of 1461 genes in the postsynaptic density and associated complexes for an enriched association with intelligence. These were ascertained in 3511 in iduals (the Cognitive Ageing Genetics in England and Scotland (CAGES) consortium) phenotyped for general cognitive ability, fluid cognitive ability, crystallised cognitive ability, memory and speed of processing. By analysing the results of a genome wide association study (GWAS) using Gene Set Enrichment Analysis, a significant enrichment was found for fluid cognitive ability for the proteins found in the complexes of N -methyl-D-aspartate receptor complex P =0.002. Replication was sought in two additional cohorts ( N =670 and 2062). A meta-analytic P -value of 0.003 was found when these were combined with the CAGES consortium. The results suggest that genetic variation in the macromolecular machines formed by membrane-associated guanylate kinase (MAGUK) scaffold proteins and their interaction partners contributes to variation in intelligence.
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Louie van de Lagemaat.