Comparative genome and proteome analysis of brain tissue from MK-801-treated rats

Abstract

Symptoms of intoxication with non-competitive N-methyl-D-aspartate (NMDA)-receptor antagonists, closely mimic symptoms in patients with schizophrenia, and therefore [+]-5-methyl-10,11-dihydro-5H-dibenzo-[a,d]-cycloheptene-5,10-iminehydrogen-maleate (MK-801, dizocilpine) treated rodents are often used as a model for schizophrenia. To investigate if administration of the NMDA receptor antagonist MK-801 to rats would induce messenger ribonucleic acid (mRNA) or protein disturbances mimicking those observed in schizophrenic patients, complementary deoxyribonucleic acid (cDNA) microarrays and two-dimensional gel-electrophoresis in combination with mass spectrometry were used, respectively. MK-801-induced changes in mRNA and protein levels were screened in the cortex, and protein levels in the thalamus, of MK-801-treated rats. Some of the altered proteins were unique for this model, and some previously found to be associated with schizophrenia were identified, displaying the utility of genomic and proteomic methods for biochemical studies on MK-801-treated rats as a model for schizophrenia. However, different proteins were altered at different treatment times of MK-801. For this reason, a study was designed to analyze how acute and subchronic MK-801-treatment to rats affected the protein profiles on rat thalamic proteome. Our results showed that the levels of many proteins were unaffected after one acute injection of MK-801 and that different treatment times of MK-801 to rats gave altered protein patterns. The effects of protein levels in thalamus of one typical (haloperidol) and one atypical (clozapine) antipsychotic on MK-801-treated rats were studied to investigate if these antipsychotic compounds would reverse the development of biochemical disturbances found in MK-801-treated rats. The protein changes induced by MK-801 treatment were reversed by clozapine and haloperidol in thalamus. In cortex, clozapine reversed all three protein changes induced by MK-801, and haloperidol reversed two out of three protein changes. In conclusion, proteomic and genomic studies on MK-801-treated rodents show a potential for further evaluating the MK-801 model of schizophrenia, by studying gene and protein alterations in the brain.