Downregulation of oligodendrocyte transcripts is associated with impaired prefrontal cortex function in rats

Abstract

Abnormalities of brain white matter and oligodendroglia are among the most consistent findings in schizophrenia (Sz) research. Various gene expression microarray studies of post-mortem Sz brains showed a downregulation of myelin transcripts, while imaging and microscopy studies demonstrated decreases in prefrontal cortical (PFC) white matter volume and oligodendroglia density. Currently, the extent to which reduced oligodendrocyte markers contribute to pathophysiological domains of Sz is unknown. We exposed adolescent rats to cuprizone (CPZ), a copper chelator known to cause demyelination in mice, and examined expression of oligodendrocyte mRNA transcripts and PFC-mediated behavior. Rats on the CPZ diet showed decreased expression of mRNA transcripts encoding oligodendroglial proteins within the medial PFC, but not in the hippocampus or the striatum. These rats also displayed a specific deficit in the ability to shift between perceptual dimensions in the attentional set-shifting task, a PFC-mediated behavioral paradigm modeled after the Wisconsin Card Sorting Test (WCST). The inability to shift strategies corresponds to the deficits exhibited by Sz patients in the WCST. The results demonstrate that a reduction in oligodendrocyte markers is associated with impaired PFC-mediated behaviors. Thus, CPZ exposure of rats can serve as a model to examine the contribution of oligodendrocyte perturbation to cognitive deficits observed in Sz.

Figure 1

CPZ intake and weight gain of ASST rats. A. Average food intake between P30 and P56. Chow was provided ad libitum until P44. Starting at P45, food restriction was implemented to increase motivation for food-digging in the ASST. During food restriction, enough food was provided to sustain weight. B. Representative growth curve for CPZ and control rats. Until P44, the growth curve was in line with the growth curve for male Sprague Dawley rats provided by Charles River Laboratories. All data in average ± SD of control (open circles; n=10) and CPZ-fed rats (black circles; n=8).

Figure 2

Hierarchical clustering of PFC samples with probesets of myelin transcripts. Twenty-six probesets of myelin transcripts (Table 3) were used for hierarchical clustering of all samples used for gene array analysis. Samples clustered according to treatment group, demonstrating the specific effect of CPZ on the expression of oligodendrocyte markers.

Figure 3

Real time quantitative PCR results after 15 days of exposure to 0.2% CPZ in PFC (A), hippocampus (C) and striatum (E), and gene array results in PFC (B) and hippocampus (D) of control rats (open bars), and rats fed with CPZ chow (black bars). (F) Real time quantitative PCR results after 26 days of exposure to 0.2% CPZ in the PFC. For Q-PCR, all transcript levels were normalized to an average of 3 loading controls, β-actin (Actb), alpha-tubulin (Tuba1a) and general transcription factor IIB (Gtf2b). Mean normalized expression values of six independent samples per group + SD are plotted. *p<=0.05, **p<=0.01, ***p<=0.001. MAG, myelin-associated glycoprotein; MBP, myelin basic protein; MOBP, myelin-associated oligodendrocytic basic protein; MOG, myelin oligodendrocyte glycoprotein; PLP, proteolipid protein; GFAP, glial fibrillary acidic protein.

Figure 4

Locomotor activity in the open field. Open field distance traveled was measured in 5 minute bins on P43, after 2 weeks of CPZ exposure, (A), and on P57, after 4 weeks of CPZ exposure and completion of the ASST, (C). Vertical movements were charted in 5 minute bins on P43, (B), and on P57, (D). All inserts show data accumulated over one hour. All data in average + SEM of control (open bars; n=6) and CPZ-fed rats (black bars; n=5).

Figure 5

Trials to reach criterion performance for all phases of the ASST. Values represent the mean + SEM of control (open bars, n=10) and CPZ-intake rats (black bars, n=8). ***p<=0.001. See Table 1 for abbreviations.