Although the etiology of schizophrenia is known to be linked with the disturbance of glutamatergic and dopaminergic neurotransmission, little is known about the relationship between gene expression and the disease process. To identify genes related to abnormalities in glutamatergic and dopaminergic ...
Although the etiology of schizophrenia is known to be linked with the disturbance of glutamatergic and dopaminergic neurotransmission, little is known about the relationship between gene expression and the disease process. To identify genes related to abnormalities in glutamatergic and dopaminergic function, we investigated the effects of olanzapine in the changes of mRNA levels in the animal model of schizophrenia, using a high-density DNA microarray. Olanzapine (3.0 mg/kg, i.p.) significantly reduced hyperlocomotive activities, which was induced by MK-801 (1.0 mg/kg, i.p.). We identified that the expression of 719 genes were significantly altered more than two folds in the prefrontal cortex of the rats treated with MK-801. We selected 15 genes out of them by the changes of the expression pattern in the treatment of Olanzapine and/or MK801 for the further confirmation in RT-PCR. The administration of MK-801 increased the expression of 7 genes (NOS3, Hspb1, Hspa1a, CRH, Serpine1, Igfbp6, Snf1lk) and decreased the expression of 1 gene (Aldh1a2), which was attenuated by olanzapine. One gene (Prss12) was up-regulated after olanzapine treatment although it did not show the significant changes after MK-801 treatment. These results showed that antipsychotic drug, such as olanzapine, may alter the gene expression patterns, which were accompanied by MK-801-induced psychosis. Our results also provide us high-density DNA microarray technology could be potential approaches to find the candidate molecules for the therapeutics and also for the early diagnosis of psychiatric diseases.
Although the etiology of schizophrenia is known to be linked with the disturbance of glutamatergic and dopaminergic neurotransmission, little is known about the relationship between gene expression and the disease process. To identify genes related to abnormalities in glutamatergic and dopaminergic function, we investigated the effects of olanzapine in the changes of mRNA levels in the animal model of schizophrenia, using a high-density DNA microarray. Olanzapine (3.0 mg/kg, i.p.) significantly reduced hyperlocomotive activities, which was induced by MK-801 (1.0 mg/kg, i.p.). We identified that the expression of 719 genes were significantly altered more than two folds in the prefrontal cortex of the rats treated with MK-801. We selected 15 genes out of them by the changes of the expression pattern in the treatment of Olanzapine and/or MK801 for the further confirmation in RT-PCR. The administration of MK-801 increased the expression of 7 genes (NOS3, Hspb1, Hspa1a, CRH, Serpine1, Igfbp6, Snf1lk) and decreased the expression of 1 gene (Aldh1a2), which was attenuated by olanzapine. One gene (Prss12) was up-regulated after olanzapine treatment although it did not show the significant changes after MK-801 treatment. These results showed that antipsychotic drug, such as olanzapine, may alter the gene expression patterns, which were accompanied by MK-801-induced psychosis. Our results also provide us high-density DNA microarray technology could be potential approaches to find the candidate molecules for the therapeutics and also for the early diagnosis of psychiatric diseases.
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제안 방법
Hybridized slides were scanned with the Axon Instruments GenePix 4000B scanner and the scanned images were analyzed with the software program GenePix Pro 5.1 (Axon, CA) and GeneSpring GX 7.3.1 (Sillicongenetics, CA). Spots that were judged as substandard by visual examination of each slide were flagged and excluded from further analysis.
Although there have been several studies of gene expression in brain with microarray, most of them have investigated gene expression change by only one compound, MK-801 or other antipsychotics25,32,33. In these studies, although several novel gene functions were revealed and confirmed the relationship in synaptic transmission, they used the microarray consisting small numbered genes or they showed the expression change of the selected gene. We have investigated the global gene expression change using high density microarray OpArray Rat genome 27K (OPRNV3, Operon Biotechnologies, GmbH).
Although a number of brain regions have been implicated in the pathophysiology of schizophrenia, the dorsal prefrontal cortex has been singled out as a major site of dysfunction on the basis of considerable clinical, neuroimaging, and postmortem studies and has thus been focused to recent microarray efforts25,28.In this study, we detected the change of the expression pattern after olanzapine treatment in the schizophrenia animal model to propose potential candidate molecules in therapeutics.
1 software (Silicon Genetics, Redwood City, CA) for data mining. Signal intensity values for all experimental replicates on any given drug-treat were averaged and used for additional analysis. The starting data set represented 28,032 probe sets.
To confirm whether the psychomimetic rat model employed in this study are built or not properly, we performed a locomotive activity analysis using the Opto-Varimex-3 animal activity meter. We recorded the ambulatory counts and moving distance.
대상 데이터
Eight male Sprague Dawley rats with an average weight of 250 g were obtained from OrientBio, Sungnam, Korea and used for the experiment. These animals were housed in a temperature and humidity-controlled environment with a 12-h light/dark cycle and had access to food and water ad libitum.
A 384-well high-throughput analysis was performed by using the ABI Prism 7900 Sequence Detection System (PE Applied Biosystems) and white colored 384-well plates (ABgene, Hamburg, Germany) for intensification of the fluorescent signals by a factor of three. The system operates using a thermal cycler and a laser that is directed via fiber optics to each of 384 sample wells. The fluorescence emission from each sample is collected by a charge coupled device-camera and the quantitative data were analyzed using the Sequence Detection System software (SDS version 2.
성능/효과
Among the selected 15 genes, 7 genes (NOS3, Hspb1, Hspa1a, CRH, Serpine1, Igfbp6, and Snf1lk) were up-regulated, and 1 gene (Aldh1a2) was downregulated by an administration of MK-801. And olanzapine treatment attenuated MK-801-induced gene expression changes in these changes.
후속연구
The genes having similar expression pattern with up-regulated only in MK801 group or down-regulated only in MK-801 group may be related in psychosis. To verify the relationship between 719 genes and psychosis, there should be further study.
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