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Event-related oscillations as risk markers in genetic mouse models of high alcohol preference.

ABSTRACT: Mouse models have been developed to simulate several relevant human traits associated with alcohol use and dependence. However, the neurophysiological substrates regulating these traits remain to be completely elucidated. We have previously demonstrated that differences in the event-related potential (ERP) responses can be found that distinguish high-alcohol preferring from low alcohol preferring mice that resemble differences seen in human studies of individuals with high and low risk for alcohol dependence. Recently, evidence of genes that affect event-related oscillations (EROs) and the risk for alcohol dependence has emerged, however, to date EROs have not been evaluated in genetic mouse models of high and low alcohol preference. Therefore, the objective of the present study was to characterize EROs in mouse models of high (C57BL/6 [B6] and high alcohol preference 1 [HAP-1] mice) and low (DBA/2J [D2] and low alcohol preference-1 [LAP-1] mice) alcohol preference. A time-frequency representation method was used to determine delta, theta and alpha/beta ERO energy and the degree of phase variation in these mouse models. The present results suggest that the decrease in P3 amplitudes previously shown in B6 mice, compared to D2 mice, is related to reductions in evoked delta ERO energy and delta and theta phase locking. In contrast, the increase in P1 amplitudes reported in HAP-1 mice, compared to LAP-1 mice, is associated with increases in evoked theta ERO energy. These studies suggest that differences in delta and theta ERO measures in mice mirror changes observed between groups at high- and low-risk for alcoholism where changes in EROs were found to be more significant than group differences in P3 amplitudes, further suggesting that ERO measures are more stable endophenotypes in the study of alcohol dependence. Further studies are needed to determine the relationship between expression of these neurophysiological endophenotypes and the genetic profile of these mouse models.

SUBMITTER: Criado JR

PROVIDER: S-EPMC2741167 | biostudies-literature | 2009 Oct

REPOSITORIES: biostudies-literature

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Event-related oscillations as risk markers in genetic mouse models of high alcohol preference.

Criado J R JR Ehlers C L CL

Neuroscience 20090621 2

Mouse models have been developed to simulate several relevant human traits associated with alcohol use and dependence. However, the neurophysiological substrates regulating these traits remain to be completely elucidated. We have previously demonstrated that differences in the event-related potential (ERP) responses can be found that distinguish high-alcohol preferring from low alcohol preferring mice that resemble differences seen in human studies of individuals with high and low risk for alcoh ...[more]

PMID: 19540906

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Project description:The 2019 International Skeletal Dysplasia Society nosology update lists 441 genes for which mutations result in rare human skeletal disorders. These genes code for enzymes (33%), scaffolding proteins (18%), signal transduction proteins (16%), transcription factors (14%), cilia proteins (8%), extracellular matrix proteins (5%), and membrane transporters (4%). Skeletal disorders include aggrecanopathies, channelopathies, ciliopathies, cohesinopathies, laminopathies, linkeropathies, lysosomal storage diseases, protein-folding and RNA splicing defects, and ribosomopathies. With the goal of evaluating the ability of mouse models to mimic these human genetic skeletal disorders, a PubMed literature search identified 260 genes for which mutant mice were examined for skeletal phenotypes. These mouse models included spontaneous and ENU-induced mutants, global and conditional gene knockouts, and transgenic mice with gene over-expression or specific base-pair substitutions. The human X-linked gene ARSE and small nuclear RNA U4ATAC, a component of the minor spliceosome, do not have mouse homologs. Mouse skeletal phenotypes mimicking human skeletal disorders were observed in 249 of the 260 genes (96%) for which comparisons are possible. A supplemental table in spreadsheet format provides PubMed weblinks to representative publications of mutant mouse skeletal phenotypes. Mutations in 11 mouse genes (Ccn6, Cyp2r1, Flna, Galns, Gna13, Lemd3, Manba, Mnx1, Nsd1, Plod1, Smarcal1) do not result in similar skeletal phenotypes observed with mutations of the homologous human genes. These discrepancies can result from failure of mouse models to mimic the exact human gene mutations. There are no obvious commonalities among these 11 genes. Body BMD and/or radiologic dysmorphology phenotypes were successfully identified for 28 genes by the International Mouse Phenotyping Consortium (IMPC). Forward genetics using ENU mouse mutagenesis successfully identified 37 nosology gene phenotypes. Since many human genetic disorders involve hypomorphic, gain-of-function, dominant-negative and intronic mutations, future studies will undoubtedly utilize CRISPR/Cas9 technology to examine transgenic mice having genes modified to exactly mimic variant human sequences. Mutant mice will increasingly be employed for drug development studies designed to treat human genetic skeletal disorders. Significance:Great progress is being made identifying mutant genes responsible for human rare genetic skeletal disorders and mouse models for genes affecting bone mass, architecture, mineralization and strength. This review organizes data for 441 human genetic bone disorders with regard to heredity, gene function, molecular pathways, and fidelity of relevant mouse models to mimic the human skeletal disorders. PubMed weblinks to citations of 249 successful mouse models are provided.

Dataset Information

Event-related oscillations as risk markers in genetic mouse models of high alcohol preference.

Publications

Event-related oscillations as risk markers in genetic mouse models of high alcohol preference.

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