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Comparative genome- and proteome analysis of cerebral cortex from MK-801-treated rats
Linda Paulson1, Peter Martin, Anders Persson
1Department of Clinical Neuroscience, Göteborg University, Göteborg, Sweden. linda.paulson@neuro.gu.se
Abstract:
cDNA microarrays and two-dimensional gel-electrophoresis in combination with mass spectrometry, were used to screen alterations in mRNA and protein levels, respectively, in cerebral cortex of MK-801-treated rats. The rats were divided in two groups; group 1 (short-term treated) and group 2 (long-term treated). In group 1, four genes were up-regulated and five down-regulated. In group 2, seven genes were up-regulated and six down-regulated. In group 1, the levels of one protein was increased and eight proteins reduced. In group 2, the levels of two proteins were increased and four proteins reduced. Several of the altered genes (casein kinase 2, glutamic acid decarboxylase, synaptotagmin, gamma aminobutyric acid [GABA] transporter, creatine kinase, and cytochrome c oxidase) and proteins (superoxide dismutase, hsp 60, hsp 72 and gamma-enolase) have previously been connected to schizophrenia. Alterations of the genes (microglobulin, c-jun proto-oncogene, 40S ribosomal protein S19, adenosine diphosphate (ADP)-ribosylation factors, platelet-derived growth factor, fructose-bisphophate aldolase A, and myelin proteolipid) and the proteins (stathmin, H+-transp. Adenosine triphosphate (ATP) synthase, pyruvate dehydrogenase, beta-actin and alpha-enolase), have not, to our knowledge, earlier been implicated in schizophrenia pathology. Overall, these results with a combined approach of genomics and proteomics add to the validity of subchronic N-methyl-D-aspartate (NMDA)-receptor antagonist treatment as an animal model of schizophrenia.
Insights
This study used genomics and proteomics to analyze brain changes in rats treated with MK-801, a model for schizophrenia. It identified several gene and protein alterations, supporting this model for schizophrenia research.
Area of Science:
- Neuroscience
- Molecular Biology
- Genomics and Proteomics
Background:
- Schizophrenia is a complex psychiatric disorder with unclear underlying molecular mechanisms.
- N-methyl-D-aspartate (NMDA)-receptor hypofunction is a leading hypothesis in schizophrenia pathophysiology.
- MK-801 is an NMDA-receptor antagonist used to create animal models of schizophrenia.
Purpose of the Study:
- To investigate global changes in gene and protein expression in the cerebral cortex of rats following short-term and long-term MK-801 treatment.
- To identify specific molecular pathways and biomarkers associated with NMDA-receptor antagonist-induced psychosis.
- To evaluate the utility of subchronic MK-801 administration as a valid animal model for schizophrenia.
Main Methods:
- Utilized complementary high-throughput techniques: cDNA microarrays for mRNA screening and two-dimensional gel electrophoresis coupled with mass spectrometry for protein profiling.
- Analyzed gene and protein expression alterations in the cerebral cortex of two groups of rats: short-term (group 1) and long-term (group 2) MK-801 treated.
- Compared expression profiles between treated and control groups to identify differentially expressed genes and proteins.
Main Results:
- Short-term treatment revealed 4 up-regulated and 5 down-regulated genes; long-term treatment showed 7 up-regulated and 6 down-regulated genes.
- Protein analysis indicated 1 increased and 8 reduced proteins in the short-term group, and 2 increased and 4 reduced proteins in the long-term group.
- Identified known schizophrenia-associated genes/proteins (e.g., GABA transporter, creatine kinase) and novel candidates (e.g., stathmin, alpha-enolase), providing molecular insights.
Conclusions:
- The combined genomics and proteomics approach revealed significant alterations in mRNA and protein levels in the rat cerebral cortex upon MK-801 treatment.
- The identified molecular changes, including both known and novel targets, support the validity of subchronic NMDA-receptor antagonist treatment as an animal model for schizophrenia.
- These findings contribute to a deeper understanding of the molecular underpinnings of schizophrenia and offer potential targets for future therapeutic strategies.