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Molecular Evidence for Mitochondrial Dysfunction in Bipolar Disorder
Christine Konradi, PhD;
Molly Eaton, BA;
Matthew L. MacDonald, BS;
John Walsh, MS;
Francine M. Benes, MD, PhD;
Stephan Heckers, MD
Arch Gen Psychiatry. 2004;61:300-308.
ABSTRACT
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Background The disease mechanism of bipolar disorder remains unknown. Recent studies have provided evidence for abnormal gene expression in bipolar disorder.
Objective To determine the expression of 12 558 nuclear genes in the human hippocampus in healthy control subjects and those with bipolar disorder or schizophrenia.
Design We used gene arrays to study messenger RNA expression. Data were verified with a real-time quantitative polymerase chain reaction assay.
Subjects We studied 10 healthy control subjects, 9 subjects with bipolar disorder, and 8 subjects with schizophrenia.
Results The expression of nuclear messenger RNA coding for mitochondrial proteins was significantly decreased in the hippocampus in subjects with bipolar disorder but not in those with schizophrenia. Subjects with bipolar disorder were characterized by a pronounced and extensive decrease in the expression of genes regulating oxidative phosphorylation and the adenosine triphosphate–dependent process of proteasome degradation.
Conclusions These findings point toward a widespread dysregulation of mitochondrial energy metabolism and downstream deficits of adenosine triphosphate–dependent processes in bipolar disorder.
INTRODUCTION
Bipolar disorder affects approximately 0.5% of the world population, often leading to recurrent illness and a marked decline in social function.1 The clinical features of bipolar disorder (ie, recurrent episodes of depression and either full-blown mania with frank psychosis or milder bouts of hypomania) have long been recognized.2 However, the etiologic and disease mechanisms remain unknown. For example, bipolar disorder shows a high degree of heritability (approximately 0.8%), and several studies have reported linkage of bipolar disorder to chromosomal loci, but not a single locus has repeatedly been linked to bipolar disorder.3
Recent spectroscopic studies have provided evidence for bipolar disorder as a disease of mitochondrial energy metabolism,4 including decreased pH5 and decreased high-energy phosphates6-7 in the frontal and temporal lobes of these patients. Such mitochondrial dysfunction in bipolar disorder could be due to an abnormal expression of nuclear or mitochondrial genes coding for mitochondrial proteins.8 In this article, we report that the expression of nuclear messenger RNA (mRNA) coding for mitochondrial proteins is significantly decreased in the hippocampus in bipolar disorder but not in schizophrenia.
METHODS
SUBJECTS
We analyzed the expression of 12 558 nuclear genes in 3 study groups: healthy controls, subjects with bipolar disorder, and subjects with schizophrenia. Brain specimens were obtained from the Harvard Brain Tissue Resource Center (McLean Hospital, Belmont, Mass) and initially consisted of 10 subjects in each diagnostic group. Each control subject was matched with 1 subject who had schizophrenia and 1 who had bipolar disorder for age and postmortem interval to ensure homogeneity of the groups. One subject with bipolar disorder and 1 subject with schizophrenia were excluded from the study because they did not provide sufficient RNA quality, as assessed by the 3'/5' ratio of glyceraldehyde-3-phosphate dehydrogenase (>4), 3'/5' ratio of  -actin (>4), and percentage (<37%) of "gene-present calls" (the percentage of genes on the array that were above the detection limit in a sample).
All diagnoses were established by 2 psychiatrists at the Harvard Brain Tissue Resource Center via retrospective review of all available medical records and extensive questionnaires about social and medical history completed by family members of the donors. We applied the criteria of Feighner et al9 for the diagnosis of schizophrenia and that of the DSM-III10 for the diagnosis of schizoaffective disorder and bipolar disorder. Probands with a documented history of substance dependence or neurological illness were excluded from the study. During our study it became evident that the documentation of 1 subject with schizophrenia was not sufficient to verify the diagnosis, and that case had to be excluded.
One hemisphere of each brain underwent a comprehensive neuropathologic examination, which revealed no evidence of stroke, tumor, infection, or neurodegenerative changes. After exclusion of 3 cases (insufficient RNA quality in 2 cases and insufficient documentation of the psychiatric history in 1 case), the final sample sizes were 10 control subjects, 9 subjects with bipolar disorder, and 8 subjects with schizophrenia (Table 1).
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Table 1. Demographics and Microarray Quality Control Data
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TISSUE PREPARATION AND RNA EXTRACTION
All brains were transported on wet ice and dissected immediately on arrival by specially trained staff at the Harvard Brain Tissue Resource Center using a standard protocol (see http://www.brainbank.mclean.org/ for details). A coronal block of the hippocampus was obtained at the level of the lateral geniculate nucleus, frozen in liquid nitrogen vapor, and stored at -80°C. Mean ± SD storage time was 31 ± 14 months with no significant difference between groups. Blocks were trimmed to include only the dentate gyrus and cornu ammonis sectors 1 through 4 without adjacent white matter of the parahippocampal gyrus. Twenty-five slices (10 µm thick) were cut from each hippocampal block in a cryostat and used for RNA extraction.
Human hippocampal RNA was prepared according to the protocol provided by Affymetrix (Santa Clara, Calif). The RNA was extracted from 50 to 100 mg of tissue with an extraction kit (RNAgents kit; Promega, Madison, Wis). The total yield of RNA was the same in all 3 groups. The RNA quality was assessed using an analytical gel and a bioanalyzer (Agilent Technologies, Palo Alto, Calif). We used 8 µg of total RNA for complementary DNA synthesis with a double-stranded complementary DNA synthesis kit (SuperScript; Invitrogen Corp, Carlsbad, Calif), and in vitro transcription was performed with an RNA transcript labeling kit (Enzo IVT kit; Enzo Biochem, Farmingdale, NY). Both the schizophrenia group and the bipolar disorder group had a 20% lower yield of biotinylated RNA. Whereas the difference was not significant in the bipolar disorder group, it reached significance in the schizophrenia group. Biotinylated RNA was fragmented and hybridized to the HG-U95Av2 array (Affymetrix) overnight at 45°C and stained on the washing station with streptavidin-phycoerythrin (Molecular Probes, Eugene, Ore) followed with a biotinylated antistreptavidin antibody (Vector Laboratories, Burlingame, Calif) and a second round of streptavidin-phycoerythrin.
Tissue preparation and RNA extraction were performed in a single batch by the same investigator to limit experimental variability. The order of samples was randomized, investigators were blinded to diagnoses, and the sample code was broken before the arrays were loaded onto the washing station to enable the investigator to randomize samples on the washing station modules.
GENE ARRAY DATA ANALYSIS
Samples were analyzed in diagnostic groups using the dChip program (http://www.dchip.org).11 Model-based expression was performed on perfect match–only data. A control sample with average intensity was chosen for normalization. We found no significant differences in the quality control criteria provided by the Data Mining Tool (Affymetrix) and dChip analyses (3'/5' ratios for glyceraldehyde-3-phosphate dehydrogenase and -actin as well as scaling factor and background) or in the ratio of 28S/18S ribosomal RNA obtained with the bioanalyzer. A significant difference was found in gene-present calls, which were lower (P = .04) in the bipolar disorder group (Table 1).
We explored expression profiles revealed by the dChip analysis further with the GenMAPP and MAPPfinder (http://www.genmapp.org) programs. GenMAPP was used to draw maps of genes in functionally related groups.12 The MAPPfinder program was used to find regulation trends in groups of genes organized according to biological process, molecular function, or cellular component, as defined by the Gene Ontology Consortium (http://www.geneontology.org). The following criteria were chosen for the MAPPfinder analysis: P<.02, with gene-present calls in more than 50% of the samples and at a fold induction higher than 1.1. For result verification, data were also computed with Affymetrix Data Mining Tool software version 3.0.
REAL-TIME QUANTITATIVE POLYMERASE CHAIN REACTION
For real-time quantitative polymerase chain reaction (PCR), complementary DNA was synthesized from 1 µg of total RNA with a synthesis system (SuperScript First-Strand Synthesis System for real-time quantitative PCR; Invitrogen Corp) using oligonucleotide deoxythymidine as the primer. A primer set for each gene was designed with the help of Primer3 software (http://www.genome.wi.mit.edu/cgi-bin/primer/primer3.cgi). Amplicons were designed to be between 100 and 150 base pairs in length. Melt curve analysis and polyacrylamide gel electrophoresis were used to confirm the specificity of each primer pair. The real-time quantitative PCR reaction was performed in accordance with described procedures13 (DNA Engine Opticon; Opticon Monitor Data Analysis Software version 1.4; MJ Research, Waltham, Mass) with a PCR kit (DyNAmo SYBR Green real-time quantitative PCR kit; Finnzymes, Espoo, Finland) in a volume of 25 µL, with 2.5 µL of 1:5 diluted complementary DNA samples and 0.3-µM primers. The PCR cycling conditions were initially 95°C for 10 minutes followed by 49 cycles at 94°C for 30 seconds, 55°C for 30 seconds, and 72°C for 30 seconds. Data were collected between 72°C and 79°C depending on amplicon melting temperature. A melt curve analysis was performed at the end of each real-time quantitative PCR experiment. Dilution curves were generated for each primer in every experiment by diluting complementary DNA twice from a control sample with a ratio of 1:3, yielding a dilution series of 1.00, 0.33, and 0.11. The logarithm of the dilution value was plotted against the cycle threshold value. Blanks were run with each dilution curve to control for cross-contamination. Dilution curves, blanks, and samples were run in duplicate. Reported values were normalized to the internal control human filamin A  (accession number NM_001456), an actin-binding protein. Human filamin A was not regulated in the gene array or quantitative PCR analysis. Seven control samples and 6 bipolar disorder samples available from the original group were used for real-time quantitative PCR.
The identical real-time quantitative PCR parameters were used for an analysis of 16 frontal lobe specimens (8 control subjects and 8 with bipolar disorder from the original study sample). Cortical tissue was removed from Brodmann area 9, and RNA was extracted as detailed previously.
RESULTS
GENE ARRAY RESULTS
We initially limited our analysis to genes expressed in at least 60% of all cases, with at least a 1.2-fold differential expression at a 90% confidence limit and significance level of P<.01. These statistical thresholds were exceptionally stringent (false discovery rate, 2.9%) and were not met by a single gene in the schizophrenia group. In contrast, the expression of 43 genes was decreased in bipolar disorder (Table 2). Using more liberal statistical thresholds, we found evidence for increased and decreased gene expression in both groups. However, for the purpose of this article we will focus on these 43 genes, in which we discovered a striking pattern: 18 genes (42%) coded for mitochondrial proteins. These included subunits of complexes I (nicotinamide adenine dinucleotide dehydrogenase in 1 gene), IV (cytochrome-c oxidase in 1 gene), and V (adenosine triphosphate [ATP] synthase in 5 genes), which carry out oxidative phosphorylation in the mitochondrial inner membrane.
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Table 2. Decreased Gene Expression in Bipolar Disorder
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In addition to the novel evidence for the abnormal regulation of nuclear genes coding for mitochondrial proteins, we also confirmed previous evidence14 of decreased expression of the 67-kd isoform of glutamic acid decarboxylase (GAD67), the enzyme synthesizing the inhibitory neurotransmitter  -aminobutyric acid (GABA) in bipolar disorder (Table 2). Furthermore, the mRNA coding for the neuropeptide somatostatin, expressed in the oriens-lacunosum/moleculare subtype of hippocampal interneurons,15 was most significantly decreased in all 43 differentially affected genes.
We performed hierarchical clustering using the dChip program to identify samples with similar expression profiles.16-17 To limit noise and increase the strength of our findings, only genes with ample variability and present calls were used for clustering (Figure 1A). Variability was set at a standard deviation greater than 4% of the mean of the expression value, and genes had to be deemed present in at least 20% of samples. A total of 216 genes met the criteria. These genes showed that bipolar disorder samples had similar genetic profiles and clustered together (P = .005).
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Figure 1. Hierarchical clustering of samples. A, All genes with a standard deviation higher than 4% of the mean of their expression value and present calls in at least 20% of samples were used for clustering (n = 216). Significant clustering of bipolar disorder samples was observed (P= .005). B, Genes known to be involved in complexes I through V of the mitochondrial respiratory chain and present in at least 20% of samples were used for clustering (n = 72). Significant clustering of bipolar disorder samples (P= .004) and control samples (P= .02) was observed. Redundant probe sets were excluded from clustering analysis. Dark-shaded rectangles indicate bipolar disorder; light-shaded rectangles, schizophrenia; open rectangles, controls; L, lithium carbonate; V, valproic acid; and ?, treatment not known.
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To further explore regulation trends in functionally related genes, we used MAPPfinder.12 Of 365 genes that were down-regulated in bipolar disorder with at least a 1.1-fold difference, P<.02, and more than 50% present calls (false discovery rate, 7.2%), 326 linked to terms defined by the Gene Ontology Consortium. Of the 6 groups that achieved a z score higher than 10, three were associated with mitochondria and 3 with the ATP-dependent process of proteasome degradation (Table 3). MAPPfinder identified 50 mRNA molecules coding for proteins located in the mitochondrial inner membrane that were in the Gene Ontology Consortium database and HG-U95Av2 array and found 17 (34%) to be decreased in bipolar disorder. Furthermore, the expression of 7 (78%) of 9 genes associated with the proton-transporting ATP synthase complex in the inner mitochondrial membrane was decreased in bipolar disorder. The dChip results were verified with Data Mining Tool software, and down-regulation of the same 2 gene families was confirmed with MAPPfinder.
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Table 3. Gene Ontology Groups
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NUCLEAR GENES RELATED TO MITOCHONDRIAL FUNCTION
To provide an unbiased review of the regulation of genes involved in energy metabolism and proteasome degradation, we used GenMAPP to draw maps of all relevant genes represented in the HG-U95Av2 array.12 These maps revealed that the decreased expression of genes related to mitochondrial function was not only pronounced but also widespread (Figure 2 and Figure 3). Similar maps for the schizophrenia group revealed that not a single one of the genes listed for oxidative phosphorylation and proteasome degradation, 62 and 28 genes, respectively, reached a probability level of P .05).
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Figure 2. Genes coding for mitochondrial proteins involved in oxidative phosphorylation. The figure includes all genes represented on the HG-U95Av2 array (Affymetrix, Santa Clara, Calif) that code for mitochondrial proteins involved in oxidative phosphorylation. Comparison of the bipolar disorder group with the control group revealed that most genes were down-regulated (indicated in blue), some were not significantly changed or had a presence call lower than 60% (indicated in yellow), and none were significantly increased. ATP indicates adenosine triphosphate; COX, cytochrome-c oxidase; Cyt, cytochrome; NADH, nicotinamide adenine dinucleotide; OSCP, oligomycin sensitivity–conferring protein; and RISP, Rieske iron-sulfur protein. A dashed line around a box indicates that the gene was represented on the chip more than once (eg, Cyt C1); if a box has more than 1 color, the various representations of the gene on the array met different criteria as indicated by the colors (eg, subunit E). Fold difference is shown to the right of the box (positive values calculated as bipolar disorder/control; negative values calculated as control/bipolar disorder).
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Figure 3. Genes coding for proteins involved in proteasome degradation. The figure includes all genes represented on the HG-U95Av2 array (Affymetrix, Santa Clara, Calif) that code for proteins involved in proteasome degradation. Comparison of the bipolar disorder group with the control group revealed that most genes were down-regulated (indicated in blue), some were not significantly changed (indicated in yellow), and none were significantly increased. See Figure 2 legend for details.
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Hierarchical clustering was performed with 72 genes known to be involved in complexes I through V of the mitochondrial respiratory chain. Significant clustering of bipolar disorder samples (P = .004) and control samples (P = .02) was observed (Figure 1B), demonstrating that these subjects had a similar profile for genes in the mitochondrial respiratory chain. No significant clustering was observed with valproic acid or lithium carbonate treatment. In a direct comparison of expression levels of mitochondrial genes, no difference was observed in patients treated with valproic acid or lithium compared with those who did not receive the drug.
Because a lower percentage of genes were deemed present in the bipolar disorder group (Table 1), we examined whether a lower percentage of gene-present calls was associated with down-regulation of genes in the mitochondrial respiratory pathway, independent of clinical diagnosis. We combined control and schizophrenia samples, sorted them according to percentage of gene-present calls, compared the 9 samples with the lower percentage of gene-present calls (mean ± SD, 42.4% ± 3.1%) with the 9 samples with a higher percentage of calls (mean ± SD, 47.3% ± 0.6%; P<.001), and performed MAPPfinder analysis. Mitochondrial membrane, mitochondrial inner membrane, and proton-transporting ATP synthase complex had z scores of 2.7 (ranked 236), 0.72 (ranked 608), and 1.6 (ranked 387), respectively. These low z scores (compared with the high z scores reported in Table 3 for the bipolar disorder group) indicate that the decreased expression of nuclear genes related to mitochondrial function cannot be explained solely by the lower percentage of gene-present calls in the bipolar disorder group.
REAL-TIME QUANTITATIVE PCR RESULTS
To confirm our finding of decreased expression of nuclear genes involved in energy metabolism and proteasome degradation in bipolar disorder, we selected 4 genes for verification in a real-time quantitative PCR assay: 2 from the mitochondrial respiratory chain and 2 proteasome subunits (Figure 4). All 4 mRNA molecules were corrected for an internal control gene (human filamin A ) and were significantly down-regulated, confirming the gene array data.
To explore whether the decreased expression of these 4 genes was specific for the hippocampus, we performed the same real-time quantitative PCR analysis in frontal cortex specimens from the same subjects (Figure 4). We found a similar pattern of decreased expression in the frontal cortex tissue in subjects with bipolar disorder.
COMMENT
Our results provide evidence for the abnormal regulation of nuclear genes coding for mitochondrial proteins in bipolar disorder. In addition, we confirm and extend previous evidence14 of abnormal gene expression in hippocampal interneurons in bipolar disorder. The decreased expression of GAD67 and somatostatin points to a specific deficit of the oriens-lacunosum/moleculare subtype of hippocampal interneurons in bipolar disorder.15 This supports the notion that a subset of hippocampal interneurons, located in the stratum oriens and terminating with apical dendrites of principal cells in conjunction with perforant pathway afferent fibers, is abnormal in bipolar disorder.
In this article, we focus primarily on the novel evidence for abnormal mitochondrial energy metabolism in bipolar disorder. First, the expression of genes coding for the enzymatic complexes governing oxidative phosphorylation is decreased in bipolar disorder. Second, the ATP-dependent process of proteasome degradation is down-regulated at the level of gene expression. This molecular evidence strengthens the hypothesis that decreased pH and high-energy phosphate levels in bipolar disorder are the result of mitochondrial dysfunction.4
It is unclear how a widespread decrease in the expression of nuclear genes coding for mitochondrial proteins could have been produced in the cases of bipolar disorder reported in this study. Although mutations in both mitochondrial18 and nuclear DNA may contribute to mitochondrial dysfunction in bipolar disorder, it is unlikely that such mutations could induce the pattern of decreased mRNA expression observed in our sample. Possible explanations of the findings are that the number of mitochondria per neuron is reduced in bipolar disorder or that a subset of neurons with high mitochondrial numbers (eg, GABAergic interneurons) is lost. That mRNA coding for the neuropeptide somatostatin, expressed in hippocampal interneurons, is also reduced might support this notion of selective neuron loss. Because glial fibrillary acidic protein mRNA, a marker of gliosis, was not altered in bipolar disorder, neuronal death would probably not be a recent event. Alternatively, mechanisms that control transcription, including the ATP-dependent process of nucleosome remodeling19 or histone acetylation and methylation,20 could be involved in widespread changes of gene expression. In this context, it is of interest that lithium and valproic acid, 2 therapeutic agents in the treatment of bipolar disorder, affect chromatin remodeling. Inositol polyphosphates, targets of lithium can modulate the activities of chromatin-remodeling complexes in vitro.21 The mood-stabilizing drug valproic acid is an inhibitor of histone deacetylase.22 The inhibition of this enzyme results in a widespread increase in gene expression, including the gene GAD67,23 which has been found to be decreased in the hippocampus in bipolar disorder in this and previous studies.14, 24 It is therefore conceivable that mechanisms of chromatin structuring are affected in bipolar disorder and are targeted by pharmaceutical compounds effective in the treatment of this disease.
Despite using all possible measures to avoid the introduction of experimental bias and although equal amounts of biotinylated RNA were used in all arrays, the percentage of gene-present calls was lower in bipolar disorder. Although not significant, data from the 28S/18S ribosomal RNA ratios and 3'/5' glyceraldehyde-3-phosphate dehydrogenase and -actin ratios might suggest reduced mRNA quality in the hippocampus in bipolar disorder. Compromised energy metabolism could account for this observation, but we cannot entirely exclude the possibility that factors inherent in postmortem studies and beyond the investigators' control might have contributed to reduced RNA quality.
Most subjects with bipolar disorder and all subjects with schizophrenia were treated with neuroleptic medication, which has supportive as well as inhibitory effects on mitochondrial function.25-27 If the genes for mitochondrial respiration were down-regulated as a result of antipsychotic drug treatment, this effect should have been more pronounced in the subjects with schizophrenia, who were treated with higher doses of antipsychotic drugs. Conversely, if antipsychotic drug treatment up-regulates genes for mitochondrial respiration, it could explain why the schizophrenia group had levels more comparable with controls. Lithium and valproic acid did not seem to be responsible for the down-regulation of genes because they did not cluster together (Figure 1B), and lithium had no such effect in an animal study.28 We consider this as evidence that the decreased gene expression in our bipolar disorder sample was not due to neuroleptic medication, lithium, or valproic acid.
Recent postmortem studies of schizophrenia have reported that the activity of oxidative enzymes associated with mitochondria, such as the malate-aspartate shuttle system29 and complex IV,30 is also decreased in the frontal cortex in subjects with schizophrenia. This suggests that disturbances in mitochondrial oxidation (at the level of gene expression, as in our study of subjects with bipolar disorder, or at the level of enzyme activity, as previously reported in those with schizophrenia) may play a broader role in psychotic disorders.
We do not know whether our finding of abnormal gene expression in bipolar disorder is specific to the hippocampus. The results of real-time quantitative PCR analysis of the frontal cortex specimens indicate that the changes reported in our article are not limited to the hippocampus. Previous studies have demonstrated abnormal gene expression in the hippocampus and cerebral cortex in bipolar disorder,31-34 but we are aware of no studies that have systematically examined the expression of genes coding for mitochondrial proteins in this disease.
It is likely that decreased nuclear gene expression governing oxidative phosphorylation has functional implications. Mitochondrial dysregulation associated with decreased oxidative phosporylation shifts metabolism toward anaerobic energy production via glycolysis, increasing lactate levels and pH and leading to reactive oxygen species, glutamate excitotoxicity, and apoptosis.35 Similarly, decreased expression of genes coding for proteins of the ubiquitin-proteasome system has functional implications, among them an impairment of synapse remodeling.36 Further studies should test the hypothesis that the pronounced and widespread decrease of mRNA coding for mitochondrial and proteasome proteins leads to abnormal protein concentration and function. It appears that our finding of a decreased expression of genes involved in mitochondrial function and proteasome degradation provides potential targets for the development of novel drug compounds in the treatment of bipolar disorder.
AUTHOR INFORMATION
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Corresponding author and reprints: Christine Konradi, PhD, McLean Hospital, Mailman Research Center, 115 Mill St, Belmont, MA 02478 (e-mail: konradi@mclean .harvard.edu).
Submitted for publication April 30, 2003; accepted October 8, 2003.
This work was supported by grants from the National Institute of Mental Health (Dr Benes) and the Stanley Foundation (Dr Heckers), Bethesda, Md, and by a gift from Jim and Pat Poitras (Dr Konradi).
We thank Wing Wong, PhD, and Cheng Li, PhD (Department of Biostatistics, Harvard School of Public Health, Boston, Mass), for advice and access to the dChip program, and George Tejada, MS, and the members of the Harvard Brain Tissue Resource Center for experimental support.
From the Department of Psychiatry, Harvard Medical School, Boston, Mass (Drs Konradi, Benes, and Heckers); and the Laboratory of Neuroplasticity (Dr Konradi, Ms Eaton, and Mr MacDonald) and Laboratory for Structural Neuroscience (Drs Benes and Heckers and Mr Walsh), McLean Hospital, Belmont, Mass.
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