Here are also features that suggest caution. As noted above, the observed SNP and SSLP associations with levels of expression fail to surpass Bonferroni corrections for the numbers of correlated markers tested. The SNP whose variants are most studied for association with schizophrenia and individual order Vorapaxar differences in cognitive function, rs10503253, fails to display significant association with levels of CSMD1 mRNA expression. Though rs10503253 lies only ca 35 kb from the rs71534387 SSLP marker that does display associations with levels of CSMD1 expression, there is only modest linkage disequilibrium (D’ = 0.1) between these markers in the individuals whose brains we sampled here. Indeed, there is substantial variation in the patterns and extents of linkage disequilibrium across the 5′ aspects of the CSMD1 gene in ABT-737MedChemExpress ABT-737 samples from different populations (http://hapmap.ncbi.nlm.nih.gov/cgi-perl/gbrowse/hapmap3r2_B36/#search), supporting the idea that use of the markers described here will provide differing patterns of information about nearby variations in samples from distinct populations. The differences in expression associated with these markers’ alleles suggest that heterozygous and/or homozygous knockout mice with reduced expression provide valid models for common variation in CSMD1 in ways that accord nicely with their manifestation of phenotypes relevant to addiction and cognitive abilities. Based on the human associations with addiction phenotypes, it is thus of interest both that there are significant differences in cocaine conditioned place preference in the heterozygous knockout mice and that these differences display some evidence for specificity. Heterozygous CSMD1 knockout mice fail to display reductions in tests of locomotion or swimming speed that would provide confounding explanations for altered performance in tests of preference for places paired with cocaine or the Morris water maze. There is no evidence that heterozygous knockout alters the conditioned locomotion that can be exerted by cocaine during conditioned place preference testing. There is no enhanced lethality or other profound physiological alteration noted with the lifelongPLOS ONE | DOI:10.1371/journal.pone.0120908 July 14,12 /CSMD1 Variants and Addictionreductions in CSMD1 expression found in heterozygous knockouts. Others have reported only modest changes in expression of genes other than CSMD1 in initial csmd1 knockouts [21]. In csmd1 mice, we have found only modest (25?0 ) increases in cerebral cortical levels of expression of mRNAs for the two CSMD1 family members, CSMD2 and CSMD3 (ANOVA p = 0.015 and < 0.001, respectively), providing additional evidence for the modest magnitude of the adaptive brain changes caused by lifelong reductions in CSMD1 expression (JD and GRU, unpublished observations, 2013). The current results add to data from studies of mice with altered expression of other cell adhesion molecules (NrCAM [36], CDH13, PTPRD (JD, GRU et al, submitted) and receptors (nAChR5 [37]), providing increasingly-robust validation for conditioned place preference as a model for human allelic variation associated with addiction vulnerability phenotypes. The conditioned place preference results from studies of heterozygous csmd1 knockouts add significant value in confirming and extending modest-magnitude human associations that might otherwise be difficult to confirm in any other manner. These data support the working hypothesis that differences in neuronal con.Here are also features that suggest caution. As noted above, the observed SNP and SSLP associations with levels of expression fail to surpass Bonferroni corrections for the numbers of correlated markers tested. The SNP whose variants are most studied for association with schizophrenia and individual differences in cognitive function, rs10503253, fails to display significant association with levels of CSMD1 mRNA expression. Though rs10503253 lies only ca 35 kb from the rs71534387 SSLP marker that does display associations with levels of CSMD1 expression, there is only modest linkage disequilibrium (D' = 0.1) between these markers in the individuals whose brains we sampled here. Indeed, there is substantial variation in the patterns and extents of linkage disequilibrium across the 5' aspects of the CSMD1 gene in samples from different populations (http://hapmap.ncbi.nlm.nih.gov/cgi-perl/gbrowse/hapmap3r2_B36/#search), supporting the idea that use of the markers described here will provide differing patterns of information about nearby variations in samples from distinct populations. The differences in expression associated with these markers' alleles suggest that heterozygous and/or homozygous knockout mice with reduced expression provide valid models for common variation in CSMD1 in ways that accord nicely with their manifestation of phenotypes relevant to addiction and cognitive abilities. Based on the human associations with addiction phenotypes, it is thus of interest both that there are significant differences in cocaine conditioned place preference in the heterozygous knockout mice and that these differences display some evidence for specificity. Heterozygous CSMD1 knockout mice fail to display reductions in tests of locomotion or swimming speed that would provide confounding explanations for altered performance in tests of preference for places paired with cocaine or the Morris water maze. There is no evidence that heterozygous knockout alters the conditioned locomotion that can be exerted by cocaine during conditioned place preference testing. There is no enhanced lethality or other profound physiological alteration noted with the lifelongPLOS ONE | DOI:10.1371/journal.pone.0120908 July 14,12 /CSMD1 Variants and Addictionreductions in CSMD1 expression found in heterozygous knockouts. Others have reported only modest changes in expression of genes other than CSMD1 in initial csmd1 knockouts [21]. In csmd1 mice, we have found only modest (25?0 ) increases in cerebral cortical levels of expression of mRNAs for the two CSMD1 family members, CSMD2 and CSMD3 (ANOVA p = 0.015 and < 0.001, respectively), providing additional evidence for the modest magnitude of the adaptive brain changes caused by lifelong reductions in CSMD1 expression (JD and GRU, unpublished observations, 2013). The current results add to data from studies of mice with altered expression of other cell adhesion molecules (NrCAM [36], CDH13, PTPRD (JD, GRU et al, submitted) and receptors (nAChR5 [37]), providing increasingly-robust validation for conditioned place preference as a model for human allelic variation associated with addiction vulnerability phenotypes. The conditioned place preference results from studies of heterozygous csmd1 knockouts add significant value in confirming and extending modest-magnitude human associations that might otherwise be difficult to confirm in any other manner. These data support the working hypothesis that differences in neuronal con.
