Mice lacking collapsin response mediator protein 1 manifest hyperactivity, impaired learning and memory, and impaired prepulse inhibition

Abstract

Collapsin response mediator protein 1 (CRMP1) is one of the CRMP family members that are involved in various aspects of neuronal development such as axonal guidance and neuronal migration. Here we provide evidence that crmp1 (-/-) mice exhibited behavioral abnormalities related to schizophrenia. The crmp1 (-/-) mice exhibited hyperactivity and/or impaired emotional behavioral phenotype. These mice also exhibited impaired context-dependent memory and long-term memory retention. Furthermore, crmp1 (-/-) mice exhibited decreased prepulse inhibition, and this phenotype was rescued by administration of chlorpromazine, a typical antipsychotic drug. In addition, in vivo microdialysis revealed that the methamphetamine-induced release of dopamine in prefrontal cortex was exaggerated in crmp1 (-/-) mice, suggesting that enhanced mesocortical dopaminergic transmission contributes to their hyperactivity phenotype. These observations suggest that impairment of CRMP1 function may be involved in the pathogenesis of schizophrenia. We propose that crmp1 (-/-) mouse may model endophenotypes present in this neuropsychiatric disorder.

Keywords: CRMP1; comprehensive behavioral test; hyperactivity; knockout mouse; mesocortical dopaminergic transmission; prepulse inhibition; schizophrenia.

Figure 1

Increased locomotor activity of crmp1^−/− mice in the 24-h home cage monitoring and the open field test. (A) Locomotor activity of wt and crmp1^−/− mice was monitored in their home cages continuously for 1 week. The white and black areas above the graph indicate light and dark periods, respectively. (B–E) The open field test with total distance (B), vertical activity (C), center time (D), and stereotypic counts (E). Statistic analysis was performed every 30 min. The p values indicate genotype effect in two-way repeated measures ANOVA. Data are shown as mean ± s.e.m. for the indicated numbers of mice. ^*p < 0.05.

Figure 2

Hyperactivity and/or impaired emotional behaviors of crmp1^−/− mice in stressful environments. (A,B) The time spent on central part (A) and the close arms (B) in the elevated plus maze test. The p values indicate genotype effect in one-way ANOVA. (C) Immobility rate in the Porsolt forced swim test. The immobility time was recorded over a 10-min test period on day 1 and day 2. The p values indicate genotype effect in two-way repeated measures ANOVA. Data are shown as mean ± s.e.m. for the indicated numbers of mice. ^*p < 0.05.

Figure 3

Impaired learning and memory of crmp1^−/− mice. (A) Contextual and cued fear conditioning test. Freezing rate during the training phase, contextual test, and cued test were calculated. The p values indicate genotype effect in two-way repeated measures ANOVA. (B) The probe trial conducted 24 h or 12 days after the last training in the Barnes maze test. Time spent around each hole was recorded. Time spent around target hole and holes adjacent to the target was compared by paired t-test. Data are shown as mean ± s.e.m. for the indicated numbers of mice. *p < 0.05.

Figure 4

Impaired prepulse inhibition and effect of chlorpromazine in crmp1^−/− mice. (A,B) Comparison between crmp1^−/− and wt mice in prepulse inhibition test with the amplitudes of the startle response (A) and the percentage of prepulse inhibition (B). (C,D) Comparison between chlorpromazine- and saline-treated crmp1^−/− mice in prepulse inhibition test with the amplitudes of the startle response (C) and the percentage of prepulse inhibition (D). The p values indicate genotype (A,B) or drug (C,D) effect in two-way repeated measures ANOVA. Data are shown as mean ± s.e.m. for the indicated numbers of mice. ^*p < 0.05, ^**p < 0.01.

Figure 5

Enhanced methamphetamine-induced release of dopamine (DA) of crmp1^−/− mice. The extracellular concentration of DA in the prefrontal cortex of freely moving mice was determined by in vivo microdialysis. After collection of basal fractions, methamphetamine (1 mg/kg, i.p) was administrated at time 0. Dopamine concentration was expressed as a percentage of the average of that in the six baseline fractions before drug administration. Statistic analysis was performed before and after the drug administration. The p values indicate genotype effect in two-way repeated measures ANOVA. Data are shown as mean ± s.e.m. for the indicated numbers of mice. ^*p < 0.01.