ABSTRACT
A growing body of evidence suggests that mitochondrial function may be important in brain development and psychiatric disorders. However, detailed expression profiles of those genes in human brain development and fear-related behavior remain unclear. Using microarray data available from the public domain and the Gene Ontology analysis, we identified the genes and the functional categories associated with chronological age in the prefrontal cortex (PFC) and the caudate nucleus (CN) of psychiatrically normal humans ranging in age from birth to 50 years. Among those, we found that a substantial number of genes in the PFC (115) and the CN (117) are associated with the GO term: mitochondrion (FDR qv <0.05). A greater number of the genes in the PFC (91%) than the genes in the CN (62%) showed a linear increase in expression during postnatal development. Using quantitative PCR, we validated the developmental expression pattern of four genes including monoamine oxidase B (MAOB), NADH dehydrogenase flavoprotein (NDUFV1), mitochondrial uncoupling protein 5 (SLC25A14) and tubulin beta-3 chain (TUBB3). In mice, overall developmental expression pattern of MAOB, SLC25A14 and TUBB3 in the PFC were comparable to the pattern observed in humans (p<0.05). However, mice selectively bred for high fear did not exhibit normal developmental changes of MAOB and TUBB3. These findings suggest that the genes associated with mitochondrial function in the PFC play a significant role in brain development and fear-related behavior.
Subject(s)
Caudate Nucleus/growth & development , Caudate Nucleus/metabolism , Fear , Frontal Lobe/growth & development , Frontal Lobe/metabolism , Gene Expression Profiling , Genes, Mitochondrial/genetics , Adolescent , Adult , Aging/genetics , Animals , Breeding , Child , Child, Preschool , Gene Expression Regulation, Developmental , Humans , Infant , Infant, Newborn , Mice , Middle Aged , Polymerase Chain Reaction , Reproducibility of Results , Signal Transduction/genetics , Young AdultABSTRACT
BACKGROUND: Recent studies have shown similarities between schizophrenia and bipolar disorder in phenotypes and in genotypes, and those studies have contributed to an ongoing re-evaluation of the traditional dichotomy between schizophrenia and bipolar disorder. Bipolar disorder with psychotic features may be closely related to schizophrenia and therefore, psychosis may be an alternative phenotype compared to the traditional diagnosis categories. METHODS: We performed a cross-study analysis of 7 gene expression microarrays that include both psychosis and non-psychosis subjects. These studies include over 400 microarray samples (163 individual subjects) on 3 different Affymetrix microarray platforms. RESULTS: We found that 110 transcripts are differentially regulated (p < 0.001) in psychosis after adjusting for confounding variables with a multiple regression model. Using a quantitative PCR, we validated a set of genes such as up-regulated metallothioneins (MT1E, MT1F, MT1H, MT1K, MT1X, MT2A and MT3) and down-regulated neuropeptides (SST, TAC1 and NPY) in the dorsolateral prefrontal cortex of psychosis patients. CONCLUSION: This study demonstrates the advantages of cross-study analysis in detecting consensus changes in gene expression across multiple microarray studies. Differential gene expression between individuals with and without psychosis suggests that psychosis may be a useful phenotypic variable to complement the traditional diagnosis categories.
Subject(s)
Gene Expression Regulation , Metallothionein/genetics , Oligonucleotide Array Sequence Analysis , Prefrontal Cortex/physiopathology , Psychotic Disorders/genetics , Aged , Bipolar Disorder/genetics , Cadaver , Female , Humans , Male , Mental Disorders/classification , Mental Disorders/genetics , Oligonucleotide Array Sequence Analysis/standards , Patient Selection , Phenotype , Polymerase Chain Reaction , Postmortem Changes , Psychotic Disorders/classification , RNA, Messenger/genetics , Reference Values , Schizophrenia/classification , Schizophrenia/geneticsABSTRACT
Total RNA was extracted from 105 individual postmortem human brain samples representing a range of postmortem conditions. To improve upon parameters currently used to screen for RNA quality, electropherogram patterns generated by the Agilent Bioanalyzer 2100 were compared to the average score in random hexamer-primed reverse transcription real-time PCR for four housekeeping genes in each RNA sample. The ribosomal ratio (28S to 18S) was found to be unrelated to the housekeeping gene score (r = -0.06; P = 0.50), and there was no threshold value in the ratio that could be applied to effectively categorize the RNA degradation. Although the housekeeping gene score correlated significantly with the percentage of area in the electropherogram corresponding to moderate to high molecular weight intact mRNA (r = 0.41; P = 0.0001), the best discriminator was determined to be the ratio of the 18S peak height to the highest peak in the tRNA to 18S rRNA baseline. Applying a lower boundary of 2.12 for the ratio allowed for the screening out of samples with the lowest housekeeping gene scores without excluding better-quality samples. This measure represents a marked improvement over the 28S to 18S ratio, which proved to be a misleading indicator of the state of the mRNA for use in random hexamer-primed reverse transcription PCR.
