Nteractions (p = 2.0 x 10-13). Memory: Morris water maze: Mice of all csmd1 genotypes swam through the Morris water maze apparatus with similar velocities (Table M in S2 Table; p = 0.106). Averaged daily latencies to reach the platform during the learning phase of the task were significantly longer in the homozygous csmd1 knockouts (Fig 6; Table K in S2 Table; repeated measures ANOVAPLOS ONE | DOI:10.1371/journal.pone.0120908 July 14,9 /CSMD1 Variants and AddictionFig 5. CSMD1 knockouts display differences in locomotion during the 20 min conditioning sessions when confined to 20 x 20 cm portions of the conditioned place ICG-001 dose preference boxes after receiving their first saline or cocaine injections. Saline-injected CSMD1 knockouts displayed significantly increased locomotion (p = 0.002) in comparison to mice of other genotypes. Significant effects of cocaine dose and gender were identified in ANCOVA of data from cocaine-injected mice of all genotypes (p = 5.5 x 10-15 and 0.009, respectively). There was a trend towards genotype * dose interaction (p = 0.054). Values are mean +/- SEM of the number of m traveled. doi:10.1371/journal.pone.0120908.ggenotype?day interaction p = 0.004). Effects were especially notable during the first day of training (Fig 6 inset; Table L in S2 Table). Latencies during the first trial on this first day were similar across genotypes. Wild type and heterozygote knockouts improved performance during the day, but homozygote knockout mice failed to improve performance. These differences reached the margin of statistical significance (repeated measures ANOVA genotype ?trial interaction p = 0.058). These results are consistent with at least some results from some of the studies of cognitive associations with human CSMD1 variants [20,23,24] and cognitive tests of mixed-background csmd1 knockouts reported from other laboratories [21,27]. Despite the longer latencies to find the PX-478 biological activity hidden platform during the acquisition phase of testing, the homozygous csmd1 knockouts did not display significantly worse performance during probe trials in which the platform was removed (Table M in S2 Table; distance from platform location p = 0.854, time in target quadrant p = 0.909).DiscussionOur current results document 15?5 differences in levels of expression of CSMD1 in postmortem brains of individuals with common CSMD1 genotype marker alleles that lie near CSMD1 markers that have been associated with substance dependence, ability to quit smoking and vulnerability to developing schizophrenia. These nominally-significant associations do not reach Bonferroni-corrected statistical significance. In csmd1 knockout mice with reducedPLOS ONE | DOI:10.1371/journal.pone.0120908 July 14,10 /CSMD1 Variants and AddictionFig 6. Morris water maze performance: time to reach platform in mice with different CSMD1 genotypes. Main Fig: Averaged daily latencies ?SEM to reach the Morris water maze platform for wildtype, heterozygous and homozygous CSMD1 knockout mice (repeated measures ANOVA genotype * day interaction p = 0.004 for learning. There were no significant differences in swimming speed (see text). Inset: More detailed data showing latencies to reach the (visible) platform during the first four trials (day 1). The trend for poorer performance in the homozygous knockouts reached the margin of statistical significance (p = 0.058). doi:10.1371/journal.pone.0120908.gCSMD1 mRNA expression, there is an overall alteration in preference for places associated w.Nteractions (p = 2.0 x 10-13). Memory: Morris water maze: Mice of all csmd1 genotypes swam through the Morris water maze apparatus with similar velocities (Table M in S2 Table; p = 0.106). Averaged daily latencies to reach the platform during the learning phase of the task were significantly longer in the homozygous csmd1 knockouts (Fig 6; Table K in S2 Table; repeated measures ANOVAPLOS ONE | DOI:10.1371/journal.pone.0120908 July 14,9 /CSMD1 Variants and AddictionFig 5. CSMD1 knockouts display differences in locomotion during the 20 min conditioning sessions when confined to 20 x 20 cm portions of the conditioned place preference boxes after receiving their first saline or cocaine injections. Saline-injected CSMD1 knockouts displayed significantly increased locomotion (p = 0.002) in comparison to mice of other genotypes. Significant effects of cocaine dose and gender were identified in ANCOVA of data from cocaine-injected mice of all genotypes (p = 5.5 x 10-15 and 0.009, respectively). There was a trend towards genotype * dose interaction (p = 0.054). Values are mean +/- SEM of the number of m traveled. doi:10.1371/journal.pone.0120908.ggenotype?day interaction p = 0.004). Effects were especially notable during the first day of training (Fig 6 inset; Table L in S2 Table). Latencies during the first trial on this first day were similar across genotypes. Wild type and heterozygote knockouts improved performance during the day, but homozygote knockout mice failed to improve performance. These differences reached the margin of statistical significance (repeated measures ANOVA genotype ?trial interaction p = 0.058). These results are consistent with at least some results from some of the studies of cognitive associations with human CSMD1 variants [20,23,24] and cognitive tests of mixed-background csmd1 knockouts reported from other laboratories [21,27]. Despite the longer latencies to find the hidden platform during the acquisition phase of testing, the homozygous csmd1 knockouts did not display significantly worse performance during probe trials in which the platform was removed (Table M in S2 Table; distance from platform location p = 0.854, time in target quadrant p = 0.909).DiscussionOur current results document 15?5 differences in levels of expression of CSMD1 in postmortem brains of individuals with common CSMD1 genotype marker alleles that lie near CSMD1 markers that have been associated with substance dependence, ability to quit smoking and vulnerability to developing schizophrenia. These nominally-significant associations do not reach Bonferroni-corrected statistical significance. In csmd1 knockout mice with reducedPLOS ONE | DOI:10.1371/journal.pone.0120908 July 14,10 /CSMD1 Variants and AddictionFig 6. Morris water maze performance: time to reach platform in mice with different CSMD1 genotypes. Main Fig: Averaged daily latencies ?SEM to reach the Morris water maze platform for wildtype, heterozygous and homozygous CSMD1 knockout mice (repeated measures ANOVA genotype * day interaction p = 0.004 for learning. There were no significant differences in swimming speed (see text). Inset: More detailed data showing latencies to reach the (visible) platform during the first four trials (day 1). The trend for poorer performance in the homozygous knockouts reached the margin of statistical significance (p = 0.058). doi:10.1371/journal.pone.0120908.gCSMD1 mRNA expression, there is an overall alteration in preference for places associated w.
